global atlas on asthma

Global atlas oF asthmaP u b l i s h e d b y t h e E u r o p e a n A c a d e m y o f A l l e r g y a n d C l i n i c a l I m m u n o l o g y

w w w . e a a c i . o r g

Asthma from epidemiology,

risk factors and mechanisms to

phenotypes and management

Major current problems in asthma

Diseases associated with

asthma

Prevention and control

of asthma

JC Virchow 2 What is asthmaJM Drazen 4 History of asthma

MI Asher 7 The asthma epidemic - Global and time trends of asthma in children

J Genuneit, D Jarvis, C Flohr 10 The asthma epidemic - Global and time trends of asthma in adults

P Burney 14 Death and disability due to asthmaRG van Wijk 18 Socio-economic costs of asthma

U Wahn 21 Natural history of asthmaR Lauener 23 Genetics of asthma

ST Weiss, K Tantisira 25 Pharmacogenetics of asthmaM Akdis 28 The pathogenesis of asthma

M Triggiani, M Jutel, EF Knol 31 The underlying mechanisms of asthma

S Wenzel 34 Phenotypes & endotypes: emerging concepts on asthma heterogeneity

I Annesi-Maesano 36 Environmental risk factors for asthmaE von Mutius 39 Life style risk and protective factors for asthma

J Schwarze 42 Infections and asthmaG Roberts 45 Emerging risk and protective factors for asthma

PG Holt 48 Perinatal and early life influences on asthma developmentH Smith 52 Psychological factors and asthma

A Custovic 55 The complex network of asthma risk and protective factorsNG Papadopoulos 57 Asthma in childhood

DK Ledford 60 Asthma in the elderlyLP Boulet 65 Asthma in the elite athlete

JA Namazy, M Schatz 68 Asthma in pregnancyS Quirce, E Heffler 71 Work-related asthma

B Marku, A Papi 75 Asthma managementJ Fingleton, R Beasley 79 Asthma monitoring

CA Akdis 106 Unmet needs in asthma DJ Jackson, SL Johnston 109 Asthma exacerbations

TB Casale 112 Severe asthmaK Ohta, O Nagase 115 Adherence to asthma treatment

RS Gupta, CM Warren 118 Social determinants of asthmaHE Neffen 120 Inequities and asthma

AJ Frew 84 Atopy and asthmaPW Hellings 86 Upper airway diseases and asthma

PG Gibson 89 Asthma and obesity, the twin epidemicsML Kowalski, S Bavbek 92 Aspirin exacerbated respiratory disease

RF Lockey 95 Gastro-esophageal reflux disease and asthmaM Cazzola 98 Cardiovascular diseases and asthma

R van Ree, A Muraro 100 Food allergy and asthmaT Werfel, C Grattan 102 Skin and lung: atopic dermatitis, urticaria and asthma

KH Carlsen, KC Lødrup Carlsen 124 Primary and secondary prevention of asthmaMB Bilò, M Calderón, V Cardona 127 Allergen immunotherapy in asthma

PM O'Byrne 130 Asthma controlI Agache 132 Best buys for asthma prevention and control

T Haahtela 135 Evidence for asthma control – zero tolerance to asthma with the Finnish programmes

J Bousquet 138 The need for integrated and complimentary strategies in the political agenda

OM Yusuf 140 Policies and strategies to facilitate access to asthma diagnosis and treatment

G WK Wong 145 Policies and strategies to reduce risk factors for asthmaNC Thomson 147 Tobacco control and asthma

L Delgado, R Barros, A Moreira 151 Implementation of a healthy life style and asthmaP Eigenmann 155 Individual interventions for asthma prevention and control

D Ryan 157 The role of Primary Care in the prevention and control of asthma

B Flood, G Schäppi 161 Role of patient organisations in the control and prevention of asthma

E Valovirta 164 Social mobilisation for prevention and control of asthma S Mendis 167 Asthma in resource constrained settings

P Demoly 169 Dealing with the implementation gap for asthma prevention and control

B Samoliński, A Czupryniak 171 Generating resources for prevention and control of asthma

WW Busse 173 Asthma prevention and control: Why it should not be ignored any longer?

CA Akdis 175 Vision, roadmap and a land-marking event

Global atlas oF asthma

Published by the European Academy of Allergy and Clinical Immunology

2013

Cezmi A. AkdisIoana Agache

Editors

Editorial Board

Victòria CardonaAdnan Custovic Pascal Demoly

Jan LötvallAntonella Muraro

Nikolaos G. PapadopoulosJ. Christian Virchow

Global atlas of asthma

II

BOARD OF OFFICERS

Cezmi A. Akdis, President

Nikolaos G. Papadopoulos, Secretary General

Antonella Muraro, Treasurer

Victòria Cardona, Vice-President Communication and Membership

Pascal Demoly, Vice-President Education and Specialty

J. Christian Virchow, Vice-President Congresses

Jan Lötvall, Past President

SECTION CHAIRPERSONS

Adnan Custovic, Asthma

Clive Grattan, Dermatology

Peter W. Hellings, ENT

Edward F. Knol, Immunology

Graham Roberts, Pediatrics

Enrico Heffler, Junior Members and Affiliates

INTEREST GROUP REPRESENTATIVES

M. Beatrice Bilò

Thomas Werfel

MEMBERS AT LARGE

Ioana Agache

Sevim Bavbek

Philippe Eigenmann

Marek Jutel

MassimoTriggiani

Ronald van Ree

ADJUNCT MEMBERS

Fulvio Braido, CME Committee Chairperson

Jan de Monchy, Specialty Committee Chairperson

Jacques Gayraud, Ethics Committee Secretary

Peter Schmid-Grendelmeier, Exam Committee Chairperson

Marek Jutel, SPC Co-ordinator

Chrysanthi Skevaki, Web Editor

Michael Walker, Executive Director

EAACI Executive Committee

EAACI ExECUTIVE COMMITTEE


III

Ioana Agache, MD, PhDAssociate Professor, Faculty

of Medicine, Department of Allergy and Clinical Immunology, Transylvania University of Brasov, Romania

Mübeccel Akdis, MD, PhDSwiss Institute of Allergy and Asthma

Research (SIAF), University of Zurich, Davos, Switzerland

Cezmi A. Akdis, MDSwiss Institute of Allergy and Asthma

Research (SIAF), University of Zurich, Davos, Switzerland

Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos

Professor, Medical Faculty, University of Zurich

Cezmi A. Akdis, MDPresident of the European Academy

of Allergy and Clinical Immunology

Isabella Annesi-Maesano, MD, PhDEpidemiology of Allergic and

Respiratory Diseases DepartmentUnité Mixte de Recherche -S 707

Institut National de la Santé et de la Recherche Médicale and Université Pierre et Marie Curie, Paris, France

M. Innes Asher, MDDepartment of Paediatrics: Child

and Youth Health, Faculty of Medical and Health Sciences, The University of Auckland

Honorary Consultant Paediatrician, Starship Children’s Health

Renata Barros, PhDFaculty of Nutrition and Food

Sciences, University of Porto

Sevim Bavbek, MD Department of Immunology and

Allergy, Ankara University, School of Medicine, Ankara, Turkey

Richard Beasley, MD, PhDDirector, Medical Research Institute

of New Zealand, Wellington, New Zealand

Adjunct Professor, Victoria University of Wellington

Adjunct Professor, University of

Otago WellingtonVisiting Professor, University of

Southampton, Southampton, New Zealand

M. Beatrice Bilò, MDAllergy Unit, Department of

Immunology, Allergy & Respiratory Diseases, University Hospital Ospedali Riuniti di Ancona, Ancona, Italy

Louis-Philippe Boulet, MDInstitut Universitaire de Cardiologie

et de Pneumologie de Québec, Canada

Jean Bousquet, MD, PhDProfessor of Pulmonary Medicine,

University of Montpellier, FranceChairman of the WHO Global Alliance

Against Chronic Respiratory Diseases (GARD)

Director of the WHO Collaborating Centre for Asthma and Rhinitis in Montpellier

Chair, MeDALL (Mechanisms of the Development of Allergy, FP7)

Peter Burney, MDRespiratory Epidemiology and

Public Health, National Heart & Lung Institute, Imperial College, London, UK

William W. Busse, MDDepartment of Medicine, Section of

Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Moisés Calderón, MD, PhDSection of Allergy and Clinical

Immunology, Imperial College, NHLI, Royal Brompton Hospital, London, UK

Victòria Cardona, MD, PhDAllergy Section, Department of

Internal Medicine, Hospital Vall d’Hebron, Barcelona, Spain

Kai-Håkon Carlsen, MD, PhDUniversity of Oslo, Institute of

Clinical MedicineOslo University Hospital, Department

of Paediatrics

Norwegian School of Sport Sciences, Oslo, Norway

Thomas B. Casale, MDProfessor Of Medicine, Chief

Allergy/Immunology, Creighton University, Omaha, NE, USA

Mario Cazzola, MDUnit of Respiratory Clinical

Pharmacology, Department of System Medicine, University of Rome Tor Vergata, Italy

Adnan Custovic, MD, PhDProfessor of Allergy, University

of Manchester, Second Floor, Education and Research Centre, University Hospital of South Manchester, UK

Agnieszka CzupryniakExpert in European Programmes and

Healthcare, Warsaw, Poland

Luis Delgado, MD, PhDFaculty of Medicine, Porto UniversityCentro Hospitalar São João EPE,

Porto, Portugal

Pascal Demoly, MD, PhDProfessor of Pulmonary Medicine,

University Hospital of Montpellier, Montpellier, France

Allergy Division, Pulmonary Department, Institut National de la Santé et de la Recherche Médicale

Hôpital Arnaud de Villeneuve

Jeffrey Drazen, MDEditor-in-Chief, New England Journal

of MedicineDistinguished Parker B. Francis

Professor of Medicine, Harvard Medical School

Professor of Physiology, Harvard School of Public Health, Boston, Massachusetts, USA

Philippe Eigenmann, MDAssociate Professor at the

Department of Infants and Adolescents at the Hôpital cantonal Universitaire Genève (HUG)

Pediatric Allergy Unit, Department of Pediatrics, Children’s Hospital, University Hospitals of Geneva,

Contributors

CONTRIBUTORS


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Geneva, Switzerland

James Fingleton, MDMedical Research Fellow, Medical

Research Institute of New Zealand, Wellington, New Zealand

School of Biological Sciences, Victoria University of Wellington

Carsten Flohr, MDSt Thomas’ Hospital & King’s College

London, UK

Breda FloodPresident, European Federation of

Allergy and Airways Diseases Patients’ Associations (EFA)

Anthony J Frew, MDDept of Allergy & Respiratory

Medicine, Royal Sussex County, Hospital Brighton, UK

Jon Genuneit, MDInstitute of Epidemiology and

Medical Biometry, Ulm University, Germany

Peter G. Gibson, MBBSCentre for Asthma and Respiratory

Diseases, University of Newcastle, NSW, Australia

Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia

Clive Grattan, MDNorfolk & Norwich University

Hospital, Norwich, UK

Ruchi Gupta, MDAssociate Professor of Pediatrics,

Center for Healthcare Studies, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University

Director, Program for Maternal and Child Health

Clinical Attending Ann and Robert H. Lurie Children’s Hospital of Chicago, USA

Tari Haahtela, MD, PhDProfessor, Skin and Allergy Hospital,

Helsinki University Hospital, Finland

Enrico Heffler, MDDepartment of Medical Sciences,

Division of Allergy & Clinical Immunology, Mauriziano “Umberto I” Hospital, University of Torino, Italy

Peter W. Hellings, MD, PhDProfessor, Clinic Head, Department

of Otorhinolaryngology, Head and Neck Surgery, University Hospitals of Leuven, Catholic University of Leuven

Patrick G. Holt, MD, PhDTelethon Institute for Child Health

Research and Centre for Child Health Research, Division of Cell Biology

The University of Western Australia, Perth, Australia

David J. Jackson, MDAirway Disease Infection Section,

National Heart and Lung Institute, Imperial College, London

MRC & Asthma UK Centre in Allergic Mechanisms of Asthma

Imperial College Healthcare NHS Trust, UK

Deborah Jarvis, MDRespiratory Epidemiology and Public

Health Group, National Heart & Lung Institute, Imperial College London, UK

Sebastian L. Johnston, MD, PhDAirway Disease Infection Section,

National Heart and Lung Institute, Imperial College, London

MRC & Asthma UK Centre in Allergic Mechanisms of Asthma

Imperial College Healthcare NHS Trust, UK

Marek Jutel, MDDepartment of Clinical ImmunologyWroclaw Medical University, PolandMedical Research Institute - ALL

MED Wroclaw

Edward F. Knol, PhDDepartments of Immunology and

Dermatology / Allergology, University Medical Center Utrecht, The Netherlands

Marek L. Kowalski, MD, PhDDepartment of Immunology,

Rheumatology and Allergy, Medical University of Łódź, Poland

Roger Lauener, MDChildren’s Hospital of Eastern

Switzerland, St. Gallen, Switzerland

Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos

Children’s Hospital, Faculty of

Medicine, University of Zurich

Dennis K. Ledford, MDMabel and Ellsworth Simmons

Professor of AllergyMorsani College of Medicine,

University of South Florida James A. Haley V.A. Hospital, Tampa,

Florida, USA

Richard F. Lockey, MDDistinguished University Health

Professor Professor of Medicine, Pediatrics and

Public HealthDirector, Division of Allergy and

Immunology, Department of Internal Medicine

Joy McCann Culverhouse Chair of Allergy and Immunology

Morsani College of Medicine, University of South Florida

James A. Haley Veterans’ Hospital, Tampa, Florida, USA

Karin C. Lødrup Carlsen, MD, PhDUniversity of Oslo, Institute of

Clinical MedicineOslo University Hospital, Department

of Paediatrics

Brunilda Marku, MD, PhDRespiratory Medicine, University of

Ferrara, ItalyResearch Centre on Asthma and

COPD, Department of Clinical and Experimental Medicine, University of Ferrara, Italy

Shanthi Mendis, MD, PhDDirector a.i., Department

of Management of Noncommunicable Diseases, World Health Organization, Geneva, Switzerland

André Moreira, MDFaculty of Medicine, University of

PortoCentro Hospitalar São João EPE,

Porto, Portugal

Antonella Muraro, MD, PhDCenter for Food Allergy Diagnosis

and Treatment, Veneto Region, Department of Woman and Child Health, University of Padua, Padua, Italy

Hiroyuki Nagase, MD, PhDAssociate Professor of Medicine,

Teikyo University, Tokyo, Japan

Jennifer A. Namazy, MDScripps Clinic, San Diego, USA

Contributors


V

Hugo E. Neffen, MDHead of the Respiratory Medicine

Unit, Children´s Hospital “Orlando Alassia”, Santa Fe, Argentina

Paul M. O’Byrne, MDFirestone Institute of Respiratory

Health, St. Joseph’s Healthcare and Department of Medicine, McMaster University, Hamilton, Canada

Ken Ohta, MD, PhDPresident National Hospital

Organization Tokyo National Hospital

Visiting Professor of Medicine at Teikyo University and Showa University, Tokyo

Nikolaos G. Papadopoulos, MD, PhD

Associate Professor in Allergology- Pediatric Allergology, Head, Allergy Department, 2nd Pediatric Clinic, University of Athens, Greece

Alberto Papi, MDProfessor of Respiratory Medicine,

University of Ferrara, ItalyResearch Center on Asthma and

COPD, Department of Clinical and Experimental Medicine, University of Ferrara, Italy

Santiago Quirce, MD, PhD Head, Department of Allergy,

Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.

Graham Roberts, MDProfessor and Honorary Consultant

Paediatrician in Paediatric Allergy and Respiratory Medicine, University of Southampton, UK

Dermot Ryan, MDGeneral Practitioner, Woodbrook UKHonorary Fellow, Allergy and

Respiratory Research Group, Centre for Population Health Sciences: GP Section, University of Edinburgh.

Bolesław Samoliński, MD, PhDMedical University of Warsaw,

Poland

Georg Schäppi, PhDDirector, aha! Swiss Centre for

AllergyChristine Kühne-Center for Allergy

Research and Education (CK-

CARE), Davos

Michael Schatz, MD Chief, Department of Allergy, Kaiser

Permanente Medical Center, San Diego, USA

Jürgen Schwarze, MD Child Life and Health and MRC-

Centre for Inflammation Research, Queen’s Medical Research Institute, The University of Edinburgh, UK

Helen Smith, MDChair of Primary Care and Head

of Division of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, UK

Kelan Tantisira, MDAssistant Professor of Medicine,

Harvard Medical School, Boston, Massachusetts, USA

Channing Division of Network Medicine , Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School

Neil C. Thomson, MDProfessor, Institute of Infection,

Immunity & Inflammation, University of Glasgow

Respiratory Medicine, Gartnavel General Hospital, Glasgow, UK

Massimo Triggiani, MD, PhDDivision of Allergy and Clinical

Immunology, University of Salerno, Italy

Erkka Valovirta, MD, PhDProfessor, Department of Pulmonary

Diseases and Clinical Allergology, University of Turku, Finland

Chief Pediatrician and Pediatric Allergist, Terveystalo, Turku, Finland

Ronald van Ree, MD, PhDProfessor, Department of

Experimental Immunology and Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The Netherlands

Roy Gerth van Wijk, MD, PhDProfessor of Allergology, Section

of Allergology, Dept. of Internal Medicine, Erasmus Medical Centre, Rotterdam

J. Christian Virchow, MDDepartment of Pneumology/

Intensive Care Medicine, University Clinic, Rostock, Germany

Erika von Mutius, MD, PhDDr. von Haunersche Kinderklinik,

Ludwig Maximilian Universität München, Germany

Ulrich Wahn, MDDepartment of Pediatric Pneumology

and Immunology, Charite, Berlin, Germany

Christopher M. Warren, PhD Research Project Coordinator, Center

for Healthcare Studies, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, USA

Scott T. Weiss, MDProfessor of Medicine, Harvard

Medical School, Boston, Massachusetts, USA

Associate Director, Channing Division of Network Medicine, Brigham and Women’s Hospital

Director, Partners Center for Personalized Genetic Medicine, Partners HealthCare System

Sally Wenzel, MDProfessor of Medicine, University

of Pittsburgh, Department of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, USA

Thomas Werfel, MDHannover Medical School, Hannover,

Germany

Gary W.K. Wong, MDProfessor, Department of Paediatrics

and School of Public Health, Chinese University of Hong Kong

Prince of Wales Hospital, Hong Kong SAR, China

Osman M. Yusuf, MDChief Consultant, The Allergy &

Asthma Institute, Islamabad, Pakistan.

Member, Planning Group, Global Alliance against Respiratory Diseases (GARD)

Director & Former Chair of Research, The International Primary Care Respiratory Group

Contributors


VII

SECTION A ASTHMA FROM EPIDEMIOLOGY, RISK FACTORS AND MECHANISMS TO PHENOTYPES AND MANAGEMENT

2 What is asthmaJ. Christian Virchow

4 History of asthmaJeffrey M. Drazen

7 The asthma epidemic - Global and time trends of asthma in childrenM. Innes Asher

10 The asthma epidemic - Global and time trends of asthma in adultsJon Genuneit, Deborah Jarvis, Carsten Flohr

14 Death and disability due to asthmaPeter Burney

18 Socio-economic costs of asthmaRoy Gerth van Wijk

21 Natural history of asthmaUlrich Wahn

23 Genetics of asthmaRoger Lauener

25 Pharmacogenetics of asthmaScott T. Weiss, Kelan Tantisira

28 The pathogenesis of asthmaMübeccel Akdis

31 The underlying mechanisms of asthmaMassimo Triggiani, Marek Jutel, Edward F. Knol

34 Phenotypes & endotypes: emerging concepts on asthma heterogeneitySally Wenzel

36 Environmental risk factors for asthmaIsabella Annesi-Maesano

39 Life style risk and protective factors for asthmaErika von Mutius

42 Infections and asthmaJürgen Schwarze

45 Emerging risk and protective factors for asthmaGraham Roberts

48 Perinatal and early life influences on asthma development

Patrick G. Holt

52 Psychological factors and asthmaHelen Smith

55 The complex network of asthma risk and protective factorsAdnan Custovic

57 Asthma in childhoodNikolaos G. Papadopoulos

60 Asthma in the elderlyDennis K. Ledford

65 Asthma in the elite athleteLouis-Philippe Boulet

68 Asthma in pregnancyJennifer A. Namazy, Michael Schatz

71 Work-related asthmaSantiago Quirce, Enrico Heffler

75 Asthma managementBrunilda Marku, Alberto Papi

79 Asthma monitoringJames Fingleton, Richard Beasley

CONTENTS

Contents

SECTION B DISEASES ASSOCIATED WITH ASTHMA

84 Atopy and asthmaAnthony J. Frew

86 Upper airway diseases and asthmaPeter W. Hellings

89 Asthma and obesity, the twin epidemicsPeter G. Gibson

92 Aspirin exacerbated respiratory diseaseMarek L. Kowalski, Sevim Bavbek


VIII

SECTION C MAJOR CURRENT PROBLEMS IN ASTHMA

106 Unmet needs in asthma Cezmi A. Akdis

109 Asthma exacerbationsDavid J. Jackson, Sebastian L. Johnston

112 Severe asthmaThomas B. Casale

115 Adherence to asthma treatmentKen Ohta, Hiroyuki Nagase

118 Social determinants of asthmaRuchi S. Gupta, Christopher M. Warren

120 Inequities and asthmaHugo E. Neffen

SECTION D PREVENTION AND CONTROL OF ASTHMA

124 Primary and secondary prevention of asthmaKai-Håkon Carlsen, Karin C. Lødrup Carlsen

127 Allergen immunotherapy in asthmaM. Beatrice Bilò, Moisés Calderón, Victòria Cardona

130 Asthma controlPaul M. O’Byrne

132 Best buys for asthma prevention and controlIoana Agache

135 Evidence for asthma control – zero tolerance to asthma with the Finnish programmes Tari Haahtela

138 The need for integrated and complimentary strategies in the political agendaJean Bousquet

140 Policies and strategies to facilitate access to asthma diagnosis and treatmentOsman M. Yusuf

145 Policies and strategies to reduce risk factors for asthmaGary W.K. Wong

147 Tobacco control and asthmaNeil C. Thomson

151 Implementation of a healthy life style and asthmaLuis Delgado, Renata Barros, André Moreira

155 Individual interventions for asthma prevention and controlPhilippe Eigenmann

157 The role of Primary Care in the prevention and control of asthmaDermot Ryan

161 Role of patient organisations in the control and prevention of asthmaBreda Flood, Georg Schäppi

164 Social mobilization for prevention and control of asthma Erkka Valovirta

167 Asthma in resource constrained settingsShanthi Mendis

169 Dealing with the implementation gap for asthma prevention and controlPascal Demoly

171 Generating resources for prevention and control of asthmaBolesław Samoliński, Agnieszka Czupryniak

173 Asthma prevention and control: Why it should not be ignored any longer?William W. Busse

175 Vision, roadmap and a land-marking eventCezmi A. Akdis

Contents

95 Gastro-esophageal reflux disease and asthma

Richard F. Lockey

98 Cardiovascular diseases and asthma

Mario Cazzola

100 Food allergy and asthmaRonald van Ree, Antonella Muraro

102 Skin and lung: atopic dermatitis, urticaria and asthmaThomas Werfel, Clive Grattan


Ix

An estimated 36 million deaths, or 63% of the 57 million deaths that occurred globally in 2008, were due to noncommunicable diseases including chronic respiratory diseases. 80% of deaths (29 million) due to noncommunicable diseases occurred in low- and middle-income countries.

Global efforts to tackle the challenge of noncommunicable diseases including asthma have gained momentum since the 2011 United Nations Political Declaration on the prevention and control of noncommunicable diseases. The World Health Organization is developing a Global Plan of Action, for 2013-2020, to provide a roadmap for country-led action for prevention and control of noncommunicable diseases including chronic respiratory diseases. It will be submitted for consideration to the 66th World Health Assembly this year.

Premature death, disability, loss of income and health-care expenditure due to asthma take a toll on families, communities and national health finances. In low- and middle-income countries many people cannot access treatment for asthma, because it is prohibitively expensive. Households often then spend a substantial share of their income on hospitalization to treat exacerbations and complications of asthma.

I wish to congratulate the European Academy of Allergy and Clinical Immunology for developing the Global Atlas of Asthma. It provides simplified and useful information on a range of topics related to prevention and control of asthma including magnitude of the problem, risk factors, associated diseases, barriers to treatment and sustainable strategies to address asthma in resource constrained settings.

I hope that the knowledge prevention and control of asthma, imparted by this document to decision makers, health workers, the civil society, private sector and the public will benefit people in all countries.

Dr. Oleg Chestnov, Assistant Director General Noncommunicable Diseases and Mental Health Cluster

World Health Organization

Foreword

FOREWORD


xI

PREFACE

Asthma is a major public health problem affecting the lives of several hundred million people around the world, with an increasing prevalence in developing countries. Governments, and the general public, face huge direct and indirect costs, with major effects on macroeconomics due to health-care costs, loss of productivity and the absenteeism of patients. Unfortunately, a high number of unmet needs remain to be resolved, due to gaps in current scientific knowledge in pathophysiology and in patient care, and as a result of the global social determinants of health.

To tackle this huge global health problem, we at the EAACI decided to develop a “Global Atlas of Asthma”. With this Atlas, our aims were: to gather evidence to call attention to the burden of asthma, to warrant its recognition as a main concern in national health strategies; to demonstrate its priority as an issue for research; to describe risk factors for asthma; to evaluate the best ways to prevent and control it; to provide guidance on how to overcome barriers; and to alert political bodies to the issue of asthma to ensure a global management approach.

The “Global Atlas of Asthma” has been developed as an essential reference source for multi-sectoral use, covering all aspects of asthma, from epidemiology, risk factors and mechanisms to phenotypes and management, to major current problems in asthma, associated diseases, and asthma prevention and control. With 59 chapters written by 80 contributing authors, and containing 147 illustrations and 46 tables, the Atlas will also be a comprehensive educational tool and desktop reference for medical students, allied health workers, primary care physicians, medical industry, policy makers, patient organizations and specialists dealing with asthma and other comorbid diseases.

I would like to thank all of the authors for their contributions, the EAACI Executive Committee Members, and particularly Prof. Dr Ioana Agache, with whom working on this highly exciting project was a great pleasure, and Costel Agache and Macarena Guillamon for their focus, devotion and proficiency.

Cezmi A. Akdis President of the

European Academy of Allergy and Clinical Immunology

Section A

ASTHMA FROM EPIDEMIOLOGY, RISK FACTORS AND

MECHANISMS TO PHENOTYPES AND MANAGEMENT

* What is asthma* History of asthma* The asthma epidemic - Global and time trends of asthma

in children* The asthma epidemic - Global and time trends of asthma

in adults* Death and disability due to asthma* Socio-economic costs of asthma* Natural history of asthma* Genetics of asthma* Pharmacogenetics of asthma* The pathogenesis of asthma* The underlying mechanisms of asthma* Phenotypes & endotypes: emerging concepts on asthma

heterogeneity

* Environmental risk factors for asthma * Life style risk and protective factors for asthma* Infections and asthma* Emerging risk and protective factors for asthma* Perinatal and early life influences on asthma development* Psychological factors and asthma* The complex network of asthma risk and protective

factors* Asthma in childhood* Asthma in the elderly* Asthma in the elite athlete* Asthma in pregnancy* Work-related asthma * Asthma management* Asthma monitoring

2

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• Asthma is one of the most common chronic inflammatory disorders

• Asthma affects patients of all ages and is a serious challenge to public health and has large effects on school and work performance of patients

• Asthma symptoms can be treated effectively in many patients however, at considerable costs

• There is no cure and many patients remain uncontrolled despite available treatment

• Combined efforts in public health, basic and clinical research need to be upscaled to fight this highly prevalent and increasing disorder

Epidemiologically asthma is a very common chronic condition. Its prevalence varies worldwide but more than 5% of any investigated population suffer from asthma. In some regions this percentage is much higher. Asthma affects all ages: it is the most common chronic disease of childhood, adolescence and adulthood and affects patients in their most productive years. Everybody is either personally af-fected or will know someone who suffers from asthma. Every physi-cian will see patients with asthma during his/ her career. Asthma is a serious challenge to public health. Its direct and indirect costs are high, but the costs of not treat-ing asthma are even higher. It has detrimental influences on school and work performance and pro-ductivity. About 10% of all asthma is caused by or occurs in the work-place. As more people reach old age it is also an important disease of the elderly. Asthma not only leads to limitations in daily life, but can end fatally in some cases, espe-cially if untreated.

Pathophysiologically asthma is an inflammatory disorder of the lungs. It leads to widespread air-flow limitation. The resulting signs and symptoms are dyspnea, dis-comfort, wheezing, anxiety and

panic and occasionally fatal res-piratory arrest. The pathogenesis of asthma is highly complex and as of today incompletely understood. Based on clinical and laborato-ry findings different phenotypes have been suggested (Figure 1). Whether they all represent differ-ent features or severities of a sin-gle disease or are separate diseas-es within the syndrome of asthma remains unclear. The majority of asthma occurs on an IgE-mediat-ed background with sensitisations to inhaled allergens called allergic asthma. Asthma which occurs on a non-allergic background is termed intrinsic asthma. Asthma often re-sults in chronic persistent airway

inflammation unrelated to aller-gen contact and has features of autoimmunity. Long term chronic inflammation has been associated with airway remodelling with an increasingly fixed airflow limita-tion as a result of “scarring” of the airways.

Clinically signs and symptoms of asthma vary from patient to pa-tient. Episodic shortness of breath, wheezing and the sensation that in-spiration is no longer possible due to hyperinflation of the lungs are common. The pathophysiological equivalent in pulmonary function tests is a reduced FEV1 (Forced Ex-piratory Volume of the first second)

J. Christian Virchow University Clinic

Rostock, Germany

WHAT IS ASTHMA1

Ke y m e ssag e s

What is asthma

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What is asthma

Figure 1 Clinically observed characteristics and asthma phenotypes. (Reproduced from Agache I, Akdis C, Jutel M, et al. Untangling asthma phenotypes and

endotypes. Allergy 2012; 67:835-846; with permission from Wiley-Blackwell.)

and PEF (Peak Expiratory Flow). A circadian peak of symptoms in the early morning hours is typical. Bronchial hyperresponsiveness to non-specific airway irritants such as smoke, cold air, odours, etc. is characteristic and can be test-ed with bronchoprovocation test with histamine or methacholine. Allergic asthma is associated with increased levels of circulating total and specific IgE. Elevated numbers of eosinophils can be found in the blood, the airway mucosa and the bronchoalveolar lavage fluid. Asth-

matic symptoms and/or asthma at-tacks increase following inhalation of allergens, but can also persist in the absence of allergenic trig-gers. The fraction of NO in exhaled breath (FeNO) can be elevated in asthma. Many patients experience worsening airflow obstruction and symptoms following exercise. Some suffer from severe attacks upon ingestion of non-steroidal anti-inflammatory drugs (Aspirin Exacerbated Respiratory Disease). None of these signs or symptoms, however, is characteristic. Asthma

therefore remains a clinical diag-nosis.

Therapeutically there is no cure for asthma available. Most patients profit from inhalation therapy with little if any side effects. However, many patients with more severe asthma or failure to adhere to treatment remain uncontrolled. Brief attacks of asthma usually respond well to the inhalation of β2-agonists. Persistent asthma re-sponds to inhaled corticosteroids. Leukotriene-antagonists, theo-phylline, anti-IgE-antibodies and anticholinergic drugs can be added in more severe or therapy refracto-ry cases.

KEY REFERENCES1. Virchow JC, Pichler WJ. Aller-

gische Atemwegserkrankun-gen. In: Petter HH, Pichler WJ, Müller-Ladner, editors. Klinische Immunologie. Munchen :Urban & Fischer, 2012.

2. Agache I, Akdis C, Jutel M, Vir-chow JC. Untangling asthma phe-notypes and endotypes. Allergy 2012; 67:835-846.

3. Lommatzsch M. Airway hyperre-sponsiveness: new insights into the pathogenesis. Semin Respir Crit Care Med 2012;33:579-587.

4. Knudsen TB, Thomsen SF, Nolte H, Backer V. A population-based clin-ical study of allergic and non-aller-gic asthma. J Asthma 2009;46:91–94.

5. Tepper RS, Wise RS, Covar R, Ir-vin CG, Kercsmar CM, Kraft M, et al. Asthma outcomes: pulmonary physiology. J Allergy Clin Immunol 2012;129:S65-87.

6. Murray CS. Can inhaled corticos-teroids influence the natural his-tory of asthma? Curr Opin Allergy Clin Immunol 2008;8:77–81.

7. Bjermer L. Evaluating combina-tion therapies for asthma: pros, cons, and comparative benefits. Ther Adv Respir Dis 2008;2:149-161.

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• The term “asthma” has been in use for millennia, but the description of the condition that now bears that name has been in place since the writings of Aretæus the Cappadocian about 2000 years ago

• Both attacks and chronic dyspnea are characteristic of asthma• Treatments of asthma based on bronchial smooth muscle rela-

xation have been in use for over 200 years, with sympathomimetic reliever treatment introduced in the early 1900s

• The use of glucocorticoids to treat asthma was introduced in the mid-20th century; inhaled corticosteroid treatment was started in the late 1960s

Jeffrey M. Drazen Harvard Medical School

Boston, USA

HISTORY OF ASTHMA2

Ke y m e ssag e sTHE TERM “ASTHMA”The term “asthma” is derived from the Greek aazein, which means to pant. Before the writings of Aretae-us in the 2nd century and well into the 20th century, many physicians and lay people alike used the term “asthma” to refer to any condition characterized by acute nonphysi-ologic shortness of breath. For ex-ample, acute congestive heart fail-ure would often be termed “cardiac asthma.” Aretaeus’s and, much lat-er, Floyer’s (1698) descriptions of asthma largely match those in use today (Figure 1).

CLINICAL DESCRIPTIONSThere are two key components of the clinical description that have survived two millennia. The first is the acute asthmatic episode, also known as an asthma attack. This is the sudden onset (as quickly as sec-onds, but more usually minutes to hours) of shortness of breath often accompanied by wheezing audible to the patient and those close to him or her; this resolves spontane-ously or as a result of treatment. The second is dyspnea of much less severity between these episodes. Exercise and allergen exposure have been recognized as causes of asthma attacks over this entire re-corded history.

The physicians examining patients with asthma were able to appre-ciate wheezing long before Laen-nec’s treatise on diseases of the chest was published in 1819. With Laennec’s work, it became clear that there were many other con-ditions characterized by wheezing other than asthma.

ASTHMA TREATMENTSAnticholinergic asthma treatment was known to Floyer. At that time, patients were instructed to inhale smoke from the burning of certain plant’s containing belladonna al-kaloids. The three most common-ly used plants were known as the “sinister sisters” because, if taken in excess amounts, they could have severe side effects including death.

These were hyoscyamus, stramoni-um, and belladonna (Figure 2). Af-ter a century of disuse, long-acting muscarinic antagonists are being re-introduced into asthma treat-ment.

Sympathomimetic treatment of asthma dates from the original use of ma huang in traditional Chinese medicine, likely over 5000 years ago. The active ingredient in ma huang is ephedra, and epinephrine, first by injection and later by inha-lation, became the standard of care for acute asthma treatment. In the 1950s, inhaled isoproterenol (iso-prenaline) was introduced for over the counter sales for asthma thera-py, but high potency isoproterenol use was associated with asthma deaths (Figure 3). Restriction of

History of asthma

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Figure 1 Title page from Floyer’s classic monograph on asthma published in 1696. This contains a clear

description of the condition we now recognize as asthma.

Figure 2 “Sinister sisters” plants. Smoking the leaves from these plants has been used as an asthma remedy for

decades. a - Datura stramonium; b - Hyoscyamus niger; c - Atropa belladonna.

History of asthma

this treatment led to a reversal in asthma deaths. In the 1960s, se-lective β

2 agonists (Figure 4), such

as albuterol, became available for inhalation and now have become the standard of care. The introduc-tion of inhaled beta agonists with duration of action of over 12 hours occurred in the 1990s. Although these are highly effective thera-pies, there has been concern about their long-term safety. Large safety studies are ongoing at this time.

GLUCOCORTICOIDS AND ASTHMAThe use of adrenocorticotropic hormone (ACTH) or injections of biologically derived or synthet-ic steroids as an asthma therapy was introduced in the early 1950s. Because of the severe side effects of systemic steroid use, inhaled

glucocorticoids were introduced in asthma treatment in the 1960s (Figure 5).

TARGETED ASTHMA TREATMENTSLeukotriene modifier treatments -- both antagonists of the action of leukotriene D

4 at the CysLT1

receptor or inhibitors of the action of the enzyme ALOX-5 were intro-duced into the market in the mid-1990s. Although their impact on lung function is less than inhaled glucocorticoids, they have a mini-mal adverse event profile and their oral action has led to their reason-ably common use. Anti-IgE therapy was approved about the turn of the 21st century.

KEY REFERENCES1. Floyer JA. Treatise of the Asthma.

London: Richard Wilkin, 1698.

2. von Mutius E, Drazen JM. A pa-tient with asthma seeks medical advice in 1828, 1928, and 2012. N Engl J Med 2012;366:827-834.

3. Tattersfield AE, McNicol MW. Salbutamol and isoproterenol. A double-blind trial to com-pare bronchodilator and cardi-ovascular activity. N Engl J Med 1969;281:1323-1326.

4. Brown HM, Storey G, George WH. Beclomethasone dipropionate: a new steroid aerosol for the treat-ment of allergic asthma. Br Med J 1972;1:585-590.

5. Drazen JM, Israel E, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene path-way. N Engl J Med 1999;341:1632.

6. Speizer FE, Doll R, Heaf P. Ob-servations on recent increase in mortality from asthma. Br Med J 1968;1:335-339.

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History of asthma

Figure 3 Asthma deaths in Britain from 1952 to 1966 showing the impact of high potency isoproterenol inhalers, introduced for over the counter sales in the late 1950s and subsequently limited to prescription use in the late 1960s.

(Reproduced from Br Med J, Speizer FE, Doll R, Heaf P, 1, 335-339, Copyright 1968 with permission from BMJ Publishing Group Ltd.)

Figure 5 Data from an early case report of the effects of inhaled

glucocorticosteroids in asthma. DSCG denotes disodium cromoglycate.

(Adapted from Br Med J, Brown HM, Storey G, George WH, 1, 585-590,

Copyright 1972 with permission from BMJ Publishing Group Ltd.)

Figure 4 Chemical structures of epinephrine, the nonselective beta-adrenergic agonist, isoproterenol

(isoprenaline), and the selective beta2-agonist, albuterol (salbutamol). The components of the structure in red show the differences from the preceeding structure.

Epinephrine

Isoproterenol

Salbutamol / Albuterol

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ASTHMA CONTExTAsthma has been recognized for more than 3000 years but it is only in the last three to four decades that it has become a serious public health concern. This was precipi-tated by a new epidemic of asthma deaths in 1977, affecting New Zea-land, more than any other country, that stimulated a great deal of re-search which continues to this day. About the same time admissions to hospital for asthma were increas-ing dramatically in New Zealand, Australia, The United Kingdom, Canada and USA and the highest rates were in New Zealand chil-dren. Until two decades ago sci-entists in these countries believed that asthma affected predominant-ly people in high income countries and was negligible in developing countries.

GLOBAL VARIATIONThe International Study of Asthma and Allergies in Childhood (ISAAC) was formed to examine variation around the world in asthma and al-lergies by development of the nec-essary standardized methodology. At the time ISAAC started (1991), there were fewer than 30 centres in the world where the prevalence of asthma in children had been studied at all, and most had used

different methodologies. Through ISAAC, which, in the third phase in-cluded 237 centres in 98 countries, we now know that asthma occurs in all countries studied, with strik-ing variations in the prevalence of asthma symptoms throughout the world, up to 15-fold between coun-tries (Figure 1). Although asthma symptoms were more common in some high income countries, some low and middle income coun-tries also had high levels of asth-ma symptom prevalence. Among children with asthma symptoms, asthma is more severe in low and middle income than high income countries (Figure 2).

TIME TRENDSStudies from English-language countries in the 1990s reported increases in asthma prevalence from the 1980s, and therefore

continuing increases in prevalence were expected. Indeed, ISAAC found that asthma in children was on the increase in many countries from 1993 to 2003. However, in most high prevalence countries, particularly the English-language countries, the prevalence of asth-ma symptoms changed little dur-ing that time, and even declined in some cases. In contrast, prev-alence increased in many coun-tries over that time, especially low and middle income countries with large populations (Figure 3). The overall percentage of children and adolescents reported to have ever had asthma increased signif-icantly, possibly reflecting greater awareness of this condition and/or changes in diagnostic practice.

CONCLUSIONThe 20-year ISAAC programme

• Asthma in children is a disease of low and middle income, as well as high income countries

• Asthma in children is more severe in low and middle income countries

• Asthma in children is on the increase in many countries especially in low and middle income countries

• Further asthma surveillance and research is needed

M. Innes Asher The University of Auckland

New Zealand

THE ASTHMA EPIDEMIC - GLOBAL AND TIME TRENDS OF ASTHMA IN CHILDREN

3a

Ke y m e ssag e s

The asthma epidemic - Global and time trends of asthma in children

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has shown that childhood asthma is a common disease in both high income and lower income coun-tries. It is relatively more severe and increasing in prevalence in many lower income countries. It is vital to continue surveillance of asthma, research its causes and reach all asthma sufferers with good management as summarised in The Global Asthma Report 2011. These are the aspirations of the new Global Asthma Network.

KEY REFERENCES1. Asher MI, Montefort S, Björkstén

B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunc-tivitis,and eczema in childhood: ISAAC Phases One and Three re-peat multicountry crosssectional surveys. Lancet 2006;368:733-743.

2. ISAAC Steering Committee. Worldwide variations in the prev-alence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Resp J 1998;12: 315-335.

3. Lai CK, Beasley R, Crane J, Foliaki S, Shah J, Weiland S, et al. Global variation in the prevalence and severity of asthma symptoms: Phase Three of the Internation-al Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2009;64:476-483.

4. Pearce N, Aït-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E, et al. Worldwide trends in the preva-lence of asthma symptoms: Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2007;62:758-766.

5. The Global Asthma Report 2011. Paris, France: The International Union Against Tuberculosis and Lung Disease, 2011.

6. The Global Asthma Network http://www.globalasthmanet-work.org, accessed May 20, 2013.


Figure 2 Prevalence of symptoms of severe asthma according to the written questionnaire in the 13–14 year age group. The symbols indicate prevalence

values of <2.5% (blue square), 2.5 to <5% (green circle), 5 to <7.5% (yellow diamond) and >7.5% (red star). (Reproduced from Thorax, Lai CK, Beasley R, Crane J, et al, 64, 476-483, Copyright 2009 with permission from BMJ Publishing Group Ltd.)

Figure 1 Prevalence of current wheeze according to the written questionnaire in the 13–14 year age group. The symbols indicate prevalence values of <5%

(blue square), 5 to <10% (green circle), 10 to <20% (yellow diamond) and >20% (red star). (Reproduced from Thorax, Lai CK, Beasley R, Crane J, et al, 64, 476-483,

Copyright 2009 with permission from BMJ Publishing Group Ltd.)

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Figure 3 World map showing direction of change in prevalence of asthma symptoms for 6-7 year age-group and 13-14 year age-group. Each symbol represents a centre. Blue triangle=prevalence reduced by ≥1 SE per year. Green square=little change (<1 SE). Red triangle=prevalence increased by≥1 SE per year. (Reprinted from The Lancet, 368, Asher MI, Montefort S, Björkstén B, Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis,and eczema in childhood: ISAAC Phases One and Three repeat multicountry crosssectional surveys, 733-43, Copyright 2006, with permission from Elsevier.)

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lence of asthma symptoms, asth-ma attacks, and the use of asthma medication in the general popu-lation aged 20 to 44 years. It was conducted at different sites, most-ly in Western Europe, between 1991 and 1994. Information from 48 study centres in 22 countries showed wide variations in the prev-alence of wheeze and ‘diagnosed asthma’, the latter being defined as a report of an asthma attack or cur-rent use of asthma medication (see Table 1).

THE WORLD HEALTH SURVEY (WHS)The WHS was conducted among adults (aged ≥18 years) in 70 coun-

tries in 2002/2003. The prevalence of respiratory symptoms was as-sessed in 68 countries, and of asth-ma diagnosis in 64. The WHS adds to the ECRHS because it provides information on adult asthma in low-income countries. The survey showed that there are wide varia-tions in the prevalence of wheeze (Figure 1) and asthma (Figure 2) re-gardless of overall national income.

THE GLOBAL ALLERGY AND ASTHMA NETWORK OF ExCELLENCE (GA2LEN)The GA2LEN survey was conducted among adults aged 15-74 years in 15 European countries in 2008/09. The data on asthma prevalence

MEASURING ADULT ASTHMA FOR GLOBAL COMPARISONThe assessment of adult asthma in epidemiological studies is difficult. Use of objective markers, such as bronchial hyperreactivity, is usual-ly impracticable in large, interna-tional population-based surveys, which therefore primarily rely on the reporting of asthma symptoms like wheeze and/or a physician-di-agnosis. A complicating factor is the lack of a commonly agreed terminology for asthma symptoms across languages. Even if this could be overcome, the perception and reporting of asthma symptoms dif-fers between subjects, who come from diverse socio-cultural back-grounds. In addition, diagnostic criteria vary between physicians, for instance as a result of working in different health care systems. Furthermore, reported asthma symptoms in the elderly are diffi-cult to distinguish from symptoms of chronic obstructive pulmonary disease (COPD). To date three large international surveys have provided data to make internation-al comparisons.

THE EUROPEAN COMMUNITY RESPIRATORY HEALTH SURVEY (ECRHS)The ECRHS assessed the preva-

Ke y m e ssag e s

• Three large international surveys on adult asthma have been conducted: ECRHS I (1991-1994), WHS (2002-2003), and GA2LEN (2008-2009)

• Comparison of prevalence estimates across the surveys is difficult due to the different methods and disease definitions

• Each survey suggests substantial geographical variation in adult asthma prevalence between countries

• Analysis of the ECRHS and information from the GA2LEN survey provides some evidence of cohort-related increases in adult asthma

• Repeat surveys need to be conducted to reliably assess global time trends of adult asthma prevalence

Jon Genuneit Ulm University

Germany

Deborah Jarvis Imperial College

London, UK

Carsten Flohr St Thomas’ Hospital &

King’s College London, UK

THE ASTHMA EPIDEMIC - GLOBAL AND TIME TRENDS

OF ASTHMA IN ADULTS3b

The asthma epidemic - Global and time trends of asthma in adults

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TABLE 1

Prevalence (in %) of ‘wheeze’ and ‘diagnosed asthma’ in the European Community Respiratory Health Survey (ECRHS) and the Global Allergy and Asthma Network of Excellence (GA2LEN) *

Country CentreECRHS GA2LEN

Country CentreECRHS GA2LEN

wheeze1 dg asthma2 asthma3 wheeze1 dg asthma2 asthma3

Iceland Reykjavik 18.0 3.4 UK Caerphilly 29.8 8.0

Norway Bergen 24.6 4.3 Cambridge 25.2 8.4

Sweden Göteborg 23.2 5.8 7.1 Dundee 28.4

Stockholm 8.6 Ipswich 25.5 7.8

Umeå 19.8 6.8 11.2 London 11.4

Uppsala 19.2 6.0 9.5 Norwich 25.7 7.5

Finland Helsinki 7.8 Southampton 14.2

Estonia Tartu 26.8 2.0 Ireland Dublin 32.0 5.0

Denmark Aarhus 24.1 4.0 Kilkenny- Wexford 24.0 5.4

Odense 8.6

Poland Katowice 5.2 Greece Athens 16.0 2.9

Krakow 7.1 Italy Palermo 10.7

Lodz 6.0 Pavia 8.5 3.3

Netherlands Amsterdam 6.4 Turin 10.7 4.5

Bergen op Zoom 19.7 4.7

Verona 9.7 4.2

Spain Albacete 25.0 3.9

Geleen 20.9 4.4 Barcelona 19.2 3.1

Groningen 21.1 4.3 Galdakao 16.2 2.1

Belgium Antwerp city 20.6 4.6 Huelva 29.2 6.3

Antwerp south 12.8 2.7 Oviedo 21.0 3.6

Ghent 7.6 Seville 22.6 5.0

Germany Brandenburg 6.3 Portugal Coimbra 19.0 6.0 16.8

Duisburg 10.1 Oporto 17.7 4.3

Erfurt 13.3 2.1 Algeria Algiers 4.2 3.0

Hamburg 21.1 4.4 India Bombay 4.1 3.5

Austria Vienna 14.3 3.1 New Zealand

Auckland 25.2 10.1

France Bordeaux 15.7 5.5 Christchurch 26.7 11.2

Grenoble 14.6 3.5 Hawkes Bay 24.2 9.0

Montpellier 14.4 5.0 10.3 Wellington 27.3 11.3

Nancy 13.6 3.7 Australia Melbourne 28.8 11.9

Paris 14.5 5.1 USA Portland, Oregon

25.7 7.1

Macedonia Skopje 5.1

* Reproduced with permission of the European Respiratory Society. Eur Respir J April 1, 1996 9:687-695 and from Jarvis D, Newson R, Lotvall J, et al. Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe. Allergy 2012;67:91-98, Wiley-Blackwell.1 Age and sex standardized prevalence of a positive response to ‘Have you had wheezing or whistling in your chest at any time in the last 12 months?’ in 20-44 year olds.2 dg asthma = diagnosed asthma. Age and sex standardized prevalence of a positive response to at least one of the following: (i) ‘Have you had an asthma attack in the last 12 months?’, or (ii) ‘Are you currently taking medication for the treatment of asthma?’ in 20-44 year olds.3 Age and sex standardized prevalence of reporting ‘ever had asthma’ AND reporting at least one of the following symptoms in the last 12 months (i) wheeze or whistling in the chest, (ii) waking with chest tightness, (iii) waking with shortness of breath, and (iv) waking with an attack of coughing in 15-74 year olds.

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Figure 1 World map of the prevalence of ‘current wheezing symptoms’ 1 among 20-44 year olds in the WHS. 1 positive response to at least one of the two options in the following question: ‘During the last 12 months, have you

experienced any of the following: (i) attacks of wheezing or whistling breathing? or (ii) attacks of wheezing that came on after you stopped exercising or some other physical activity?’ (Reproduced with permission of the European Respiratory Society.

Eur Respir J February 2010 35:279-286; published ahead of print September 9, 2009, doi:10.1183/09031936.00027509.)

Figure 2 World map of the prevalence of ‘diagnosed asthma’ 1 in the WHS. 1 positive response to any of the following: (i) ‘have you ever been diagnosed with asthma (an allergic respiratory disease)?’; (ii) ‘have you ever been treated for it?’; (iii) ‘have you been taking any medications or other treatment for it during the last 2 weeks?’ (Reproduced with permission of the European Respiratory Society. Eur Respir J February 2010 35:279-286; published

ahead of print September 9, 2009, doi:10.1183/09031936.00027509.)


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from 19 centres (12 countries) fol-lowing the full study protocol are displayed in the table.

COMPARABILITY BETWEEN THE SURVEYSThe WHS used different sam-pling methods to ECRHS and GA2LEN, and ECRHS (unlike WHS and GA2LEN) studied only young adults. Different questions were employed to define the prevalence of asthma. The footnotes to the table and figures explain some of these differences.

TIME TRENDS IN ADULT ASTHMA PREVALENCENeither of these three surveys has been repeated on an international level to assess time trends in adult asthma prevalence. At single sites, repeat surveys have been conduct-ed using the ECRHS methodology. In two examples from Italy and Sweden the prevalence of diag-nosed asthma increased. Some-what contradictory, over the same period, the prevalence of wheeze decreased in Sweden but increased in Italy.

Over the last sixty years there has been a well documented cohort

related increase in asthma in chil-dren, and we would expect this to be reflected in higher asthma prevalence in adults as the affect-ed cohorts have aged. Consistent with this, there is evidence from GA2LEN that the prevalence of asthma in younger adults is high-er than in older adults in most (al-though not all) parts of Europe. An alternative explanation could be that asthma remits with aging. Within the ECRHS, data from 15 industrialized countries on age at first asthma attack were used to estimate the incidence of asthma within birth cohorts represented in the study population, suggest-ing that the cumulative incidence of asthma increased progressively across the birth cohorts from sub-jects born in 1946-1950 (Figure 3). However, the retrospective assess-ment of age at onset of asthma may be subject to recall bias and secular changes in labelling of asthma may additionally affect the results.

KEY REFERENCES1. Variations in the prevalence of

respiratory symptoms, self-re-ported asthma attacks, and use of asthma medication in the Eu-ropean Community Respiratory

Health Survey (ECRHS). Eur Respir J 1996;9:687-695.

2. Sembajwe G, Cifuentes M, Tak SW, Kriebel D, Gore R, Punnett L. National income, self-reported wheezing and asthma diagnosis from the World Health Survey. Eur Respir J 2010;35:279-286.

3. Jarvis D, Newson R, Lotvall J, Hastan D, Tomassen P, Keil T, et al. Asthma in adults and its associa-tion with chronic rhinosinusitis: the GA2LEN survey in Europe. Al-lergy 2012;67:91-98.

4. Bjerg A, Ekerljung L, Middelveld R, Dahlén S-E, Forsberg B, Frank-lin K, et al. Increased prevalence of symptoms of rhinitis but not of asthma between 1990 and 2008 in Swedish adults: comparisons of the ECRHS and GA2LEN surveys. PLoS ONE 2011;6:e16082.

5. de Marco R, Cappa V, Accordini S, Rava M, Antonicelli L, Bortolami O, et al. Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991 and 2010. Eur Respir J 2012;39:883-892.

6. Sunyer J, Antó JM, Tobias A, Bur-ney P. Generational increase of self-reported first attack of asth-ma in fifteen industrialized coun-tries. European Community Res-piratory Health Study (ECRHS). Eur Respir J 1999;14:885-891.

0 10 20 30 40Age

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Figure 3 Cumulative incidence of ‘asthma’ 1 by age at first asthma attack and birth cohort.

1 positive response to ‘Have you ever had asthma?’ (Reproduced with permission of the European

Respiratory Society. Eur Respir J October 1, 1999 14:885-891.)


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Recorded asthma mortality rates vary very widely across age groups rising (as with most causes of death) exponentially with age, rates being slightly lower among women than men at all ages (Figure 1). Death rates are also very une-ven between different regions. In 2010 the highest death rates from asthma were experienced in Oce-ania with high rates also in south and south-east Asia southern and central and east sub-Saharan Afri-ca and in north Africa the middle east and central Asia. Much lower mortality rates were observed in Australasia, Europe and North and South America (Figure 2).

Over the last two decades mor-tality rates have been falling. In 1990 the global mortality rate for asthma (age adjusted) was around 25/100,000 men and around 17/100,000 women, by 2010 these figures had fallen to around 13/100,000 for men and just over 9/100,000 for women (Figure 3). This downward trend was univer-sal, though some regions, such as Australia/New Zealand, experi-enced a relatively more rapid de-cline.

The disability associated with asthma varies with the amount of control of the condition. Well-con-

trolled asthma has relatively little effect on daily life, but uncontrolled asthma has a serious impact, esti-mated to be considerably more dis-abling than, for instance, moderate angina pectoris (Figure 4).

In many parts of the world access to medication is severely limited and lack of access to inhaled cor-

ticosteroids severely reduces the chances of asthma being adequate-ly controlled. This may explain in part why in areas such as in sub-Sa-haran Africa, where access to med-ication may be poor severe asthma is more common than would other-wise might be predicted from the prevalence of asthma (Figure 5).

Peter Burney Imperial College

London, UK

DEATH AND DISABILITY DUE TO ASTHMA4

Ke y m e ssag e s• Asthma mortality rates rise rapidly with age and are higher in

boys and men• Asthma mortality rates vary widely across different regions of

the world and are highest in Oceania and lowest in the developed economies

• Since 1990 mortality rates from asthma have been falling in all regions of the world

• Disability associated with asthma is highest in uncontrolled asthma

• Uncontrolled asthma is associated with more disability than is moderate angina pectoris, but less disability than moderate COPD or Parkinsonism

• Undertreated asthma is associated with a heavy economic and social burden

• Although many areas where asthma is common also have a high prevalence of “severe” disease, there are areas such as sub-Saharan Africa where severe asthma is relatively more common

• The relative importance depends on the prevalence of other pathologies; in Australia and New Zealand, where mortality rates are relatively low, asthma is the 15th most common cause of disability adjusted life years (DALYs) lost, whereas in South Asia where mortality rates are higher, it is the 25th cause of DALYs lost

Death and disability due to asthma

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Figure 1 Global death rates/100 000 from asthma by age in 2010. (Data from Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291

diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease

Study 2010. Lancet 2012;380:2197-2223.)

Figure 3 Global trends in age standardised mortality from asthma by sex.

Figure 4 Disability score in various chronic diseases. (Data from Salomon JA, Wang H, Freeman MK, et al. Healthy life expectancy for 187 countries, 1990-2010: a systematic analysis for the Global Burden Disease Study 2010. Lancet

2012;380:2144-2162.)

Figure 2 Male Asthma Mortality/100 000 by Global Burden of Diseases Region (2010). (Data from Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis

for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-2128.)

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causing loss of disability adjusted

life years, as in Central and East Af-

rica. Although sub-Saharan Africa

has consistently higher death rates

from asthma compared with West-

ern Europe, asthma is relatively

less important there when com-

pared with other causes of death

and disability.

KEY REFERENCES1. Lozano R, Naghavi M, Foreman K,

Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Glob-al Burden of Disease Study 2010. Lancet 2012;380:2095-2128.

2. Salomon JA, Wang H, Freeman MK, Vos T, Flaxman AD, Lopez

Figure 6 Loss of work related to asthma treatment in the GASP study. (Data from Burney P, Potts J, Aït-Khaled N, et al. A multinational study of treatment failures

in asthma management. Int J Tuberc Lung Dis 2008;12:13-18.)

The implications of this for pa-tients and for the economy can be substantial. Figure 6 shows results from a study of patients attend-ing emergency rooms for asthma, mostly in low and middle income countries. The patients’ level of treatment was compared to that recommended for the severity of their disease and they were asked how much work they had missed in the previous weeks. Over 50% of those taking two or more steps be-low the recommended treatment had missed over a day a week of work, compared with about 5% of those who were on the appropriate treatment.

There are however other determi-nants of asthma control, and these are partly unknown. In Europe the proportion of patients on inhaled corticosteroids who have uncon-trolled asthma is fairly constant at around 10%-20%, but there is wider variation in the proportion of patients who are taking inhaled corticosteroids and who are still uncontrolled, and this varies from 20% to 65% (Figure 7).

Because asthma is a common condition and one that in many instances starts very young and persists throughout life, its impact is substantial, and this impact, rel-ative to that of other diseases, is paradoxically higher in some re-gions with relatively low mortality (Figure 8). Asthma ranks in the top 20 conditions affecting the disabili-ty adjusted life years in Australasia as well as in Oceania, South East Asia and tropical Latin America, and ranks in the top 25 in North America and Western Europe as well as in North Africa and the Middle East, Southern Africa and Southern Latin America. Converse-ly, in some places, where severe disease is common, it still falls fur-ther down the rank of conditions


Figure 5 Prevalence of “severe” asthma in 13-14 year olds in the ISAAC studies. The symbols indicate prevalence values of <2.5% (blue square), 2.5 to <5%

(green circle), 5 to <7.5% (yellow diamond) and >7.5% (red star). (Reproduced from Thorax, Lai CK, Beasley R, Crane J, et al, 64, 476-483, Copyright 2009 with

permission from BMJ Publishing Group Ltd.)

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Figure 7 Percentage of patients with asthma in the European

Community Respiratory Health Survey who were uncontrolled

according to use of Inhaled Corticosteroids (ICS). (Reprinted

from J Allergy Clin Immunol, 120/6, Cazzoletti L, Marcon A, Janson C, et al, Asthma control in Europe: a

real-world evaluation based on an international population-based study, 1360-1367, Copyright 2007, with permission from

Elsevier.)

Figure 8 Importance of asthma relative to other

conditions. Rank of disability adjusted life years by region (2010). (Data from Murray CJ,

Vos T, Lozano R, et al. Disability-adjusted life years (DALYs)

for 291 diseases and injuries in 21 regions, 1990-2010:

a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197-

2223.)

AD, et al. Healthy life expectancy for 187 countries, 1990-2010: a systematic analysis for the Global Burden Disease Study 2010. Lan-cet 2012;380:2144-2162.

3. Aït-Khaled N, Auregan G, Bencha-rif N, Camara LM, Dagli E, Djank-ine K, et al. Affordability of inhaled corticosteroids as a potential barrier to treatment of asthma in some developing countries. [erratum in Int J Tuberc Lung Dis 2001;5:689]. Int J Tuberc Lung Dis 2000;4:268-271.

4. Lai CK, Beasley R, Crane J, Foliaki S, Shah J, Weiland S, et al. Global variation in the prevalence and severity of asthma symptoms: Phase Three of the Internation-al Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2009;64:476-483.

5. Burney P, Potts J, Aït-Khaled N, Sepulveda RM, Zidouni N, Bena-li R, et al. A multinational study of treatment failures in asthma management. Int J Tuberc Lung Dis 2008;12:13-18.

6. Cazzoletti L, Marcon A, Janson C, Corsico A, Jarvis D, Pin I, et al. Asthma control in Europe: a re-al-world evaluation based on an international population-based study. J Allergy Clin Immunol 2007;120:1360-1367.

7. Murray CJ, Vos T, Lozano R, Nagha-vi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and in-juries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197-2223.

Iceland

Norway

France

Germany

Belgium

Spain

Sweden

UK

Switzerland

Italy

Overallprevalence

0 10 20 30 40 50 60 70 80 90 100

Iceland

Spain

Germany

Switzerland

Italy

UK

Belgium

Sweden

Norway

France

Overallprevalence

0 10 20 30 40 50 60 70 80 90 100

% of subjects with uncontrolled asthma

ICS users [p<0.001] non-ICS users [p=0.665]

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Asthma is characterized by a ma-jor impact on patients in terms of impairment of quality of life, work and school performance. Patients may experience sleep disorders, impairment of cognitive function, depression and anxiety. The high and increasing prevalence of these disorders in particular allergic rhi-nitis and asthma may lead to sub-stantial direct and indirect costs of disease.

ECONOMIC IMPACT OF ASTHMAIn a Global Initiative of Asthma (GINA) report on the burden of asthma, it has been estimated that asthma is one of the most common chronic diseases in the world: 300 million people in the world have asthma. The number of disabili-ty-adjusted life years (DALYs) lost due to asthma worldwide has been estimated to be currently about 15 million per year. Worldwide, asth-ma accounts for around 1% of all DALYs lost, which reflects the high prevalence and severity of asthma. The number of DALYs lost due to asthma is similar to that for diabe-tes, cirrhosis of the liver, or schizo-phrenia. When ranking chronic dis-eases, asthma was the 25th leading cause of DALYs lost worldwide in 2001 (Figure 1).

An analysis of the burden of asth-ma in the US estimated the annual costs per patient at $ 1907 and the total national medical expendi-ture at $ 18 billion. The ERS White book, published in 2003 estimated the total costs of asthma in Europe at approximately € 17.7 billion per annum. The countries with the most asthma related consultations were the UK, followed by Greece and Germany. The countries with the least consultations were Po-land and Turkey. A 2012 analysis derived from the European Com-munity Respiratory Health Survey II (ECRHS II) estimated the annual costs per patient in Europe at € 1583.

An estimate of the costs of asthma

in children in 25 EU countries has been published in 2005. The total costs of asthma for the 25 coun-tries of the European Union are estimated at € 3 billion. The use of wheeze as definition of asthma leads to considerable higher costs of € 5.2 billion. Annual costs for childhood asthma per country vary widely (Figure 2).

DIRECT AND INDIRECT COSTSThe direct costs of disease com-prise the health care expenditure associated with hospitalizations, emergency visits, physician vis-its, diagnostic tests and medical treatment, whereas indirect costs include the impact on employment, loss of work productivity and oth-er social costs. The most impor-

Ke y m e ssag e s• The economic burden of asthma is substantially high• Uncontrolled asthma is an important cost-enhancing factor• Hospital admissions and medication costs are the major

components of direct costs• A national approach may be useful in reducing the burden of

asthma• Indirect costs of asthma are substantial and for a major part

caused by productivity losses• Increase of asthma prevalence and costs of medication are

responsible for the rise in the cost of illness

Roy Gerth van Wijk Erasmus Medical Centre

Rotterdam, the Netherlands

SOCIO-ECONOMIC COSTS OF ASTHMA5

Socio-economic costs of asthma

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tant cost components are hospital admissions and asthma medica-tion. Australian, US and Canadian studies found that direct costs ac-count for the greatest part of the total costs. However, the Ameri-can TENOR study focusing on se-vere and difficult to treat asthma demonstrated higher indirect than direct costs. Also, several Europe-an studies among of which a large German study demonstrated that up to 75% of the total costs of asth-ma could be attributed to indirect costs. An analysis of adult asthma in 11 ECRHS countries showed that 62.5% of the total costs were caused by working days lost and days with limited, not work relat-ed activities. These studies un-derwrite that the indirect costs of asthma are substantial (Figure 3).

COST-ENHANCING FACTORSMore than 20 studies suggest that more severe disease is a major fac-tor influencing the increase in asth-ma-related costs. Comparisons be-tween mild and severe disease may result in 1.3 - 5 fold differences. Other cost-enhancing factors com-prise poor asthma control, comor-bidity, and disability status (Figure 3).

TRENDS IN COSTSThe costs of asthma are rising. For instance, in Canada the costs of asthma increased due to a rise in prevalence and cost of medication. The increase was observed in spite of a reduction in hospitalizations and physician visits. In contrast, the National Asthma Programme in Finland has been proven to be effective in reducing the costs per patient per year by 36% in ten years.

Figure 1 Disability-adjusted life years lost due to asthma worldwide – ranking with other common disorders. GINA report Global burden of asthma 2001. (Data from Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary

of the GINA Dissemination Committee report. Allergy 2004;59:469-478.)


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KEY REFERENCES1. Masoli M, Fabian D, Holt S, Beas-

ley R. The global burden of asth-

ma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59:469-478.

Figure 2 Annual costs of childhood asthma per country. Yellow: less than 100 million €; orange: between 100 and 300 million €; red: more than 300 million

€. (Data from van den Akker-van Marle ME, Bruil J, Detmar SB. Evaluation of cost of disease: assessing the burden to society of asthma in children in the European Union.

Allergy 2005;60:140-149.)


Figure 3 Direct and indirect costs of asthma and cost-enhancing factors.

2. Sullivan PW, Ghushchyan VH, Sle-jko JF, Belozeroff V, Globe DR, Lin SL. The burden of adult asthma in the United States: evidence from the Medical Expenditure Pan-el Survey. J Allergy Clin Immunol 2011;127:363-369 e1-3.

3. European Respiratory Society. European lung white book. Hud-dersfield: European Respiratory Society Journals Ltd., 2003.

4. Accordini S, Corsico AG, Brag-gion M, Gerbase MW, Gislason D, Gulsvik A, et al. The cost of persis-tent asthma in europe: an inter-national population-based study in adults. Int Arch Allergy Immunol 2013;160:93-101.

5. van den Akker-van Marle ME, Bruil J, Detmar SB. Evaluation of cost of disease: assessing the burden to society of asthma in children in the European Union. Allergy 2005;60:140-149.

6. Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swis-ton J, et al. Economic burden of asthma: a systematic review. BMC Pulm Med 2009;9:24.

7. Chipps BE, Zeiger RS, Borish L, Wenzel SE, Yegin A, Hayden ML, et al. Key findings and clinical im-plications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regi-mens (TENOR) study. J Allergy Clin Immunol 2012;130:332-342 e10.

8. Stock S, Redaelli M, Luengen M, Wendland G, Civello D, Lauter-bach KW. Asthma: prevalence and cost of illness. Eur Respir J 2005;25:47-53.

9. Bedouch P, Marra CA, Fitzger-ald JM, Lynd LD, Sadatsafavi M. Trends in asthma-related direct medical costs from 2002 to 2007 in british columbia, Canada: a pop-ulation based-cohort study. PLoS One 2012;7:e50949.

10. Haahtela T, Tuomisto LE, Pietinal-ho A, Klaukka T, Erhola M, Kaila M, et al. A 10 year asthma programme in Finland: major change for the better. Thorax 2006;61:663-670.

Economic burden of asthma

Direct costs Indirect costs

Hospital admissions

Emergency visits

Physician visits

Diagnostics

Medication

Productivity loss• Absenteism• Presenteism• Unemployment

School days lostTravelling (time)Disability costs

Cost-enhancing factors

Asthma severityPoor asthma control

ComorbidityDisability status

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Ke y m e ssag e s• Most children with recurrent wheeze in infancy will grow into

remission• Long term outcome may be influenced by early exposure to

certain viruses (Rhinovirus, RSV)• Early domestic exposure to indoor allergens together with early

sensitization may lead to impaired lung function in school-age• Tobacco smoke exposure during pregnancy increases the risk for

long-term asthma• Atopic sensitization to indoor allergens in preschool age is a risk

factor for persistence of asthma• Strategies trying to prevent asthma up to now have not been

successful• Future initiatives for asthma-prevention should focus on viral-

triggers and tolerance-induction to indoor allergens

Ulrich Wahn Charite - University Medicine

Berlin, Germany

NATURAL HISTORY OF ASTHMA6

Natural history of asthma

The highest annual incidence of wheeze is observed during infan-cy. Long-term longitudinal cohort studies have clearly demonstrated that the vast majority of wheezy infants will not grow into a chronic asthma during the following dec-ades. However, early exposure to certain viruses like Rhinovirus or Respiratory Syncytial Virus (RSV) increase the risk of recurrent asth-matic wheeze in school-age and ad-olescence. In preschool-age differ-ent clusters of asthmatic children are emerging. The natural history of asthma is strongly determined by parental phenotypes: asthma and atopy in father and mother is associated with higher prevalence of asthma during the first two dec-ades of life. During the first years of life asthma prevalence is higher in boys. Between the age of 12 to 14 years old girls are catching up so that after adolescence most stud-ies find higher prevalence rates in females.

A number of environmental factors have been shown to significantly contribute to a poor outcome of childhood asthma. Among them do-mestic tobacco-smoke exposure, particularly during pregnancy and infancy, is clearly one of the most important risk factors. In many

adolescents asthma is associated with sensitization to indoor-aller-gens, particularly house-dust mites and cats. For children who ac-quire this sensitization during the first three years of life it has been demonstrated that the chance for long-term asthma remission is sig-nificantly reduced (Figure 1), and long function will be impaired by school-age.

Future challenges for paediatric allergists and chest physicians in-clude the need to find appropriate strategies for asthma prevention. After a variety of pharmacother-

apeutical approaches like inhaled corticosteroids, antihistamines or calcineurin inhibitors have failed, it appears likely, that future activities will have to address the role of viral infections in infancy as well as the mechanism of early sensitization or tolerance induction to indoor al-lergens (Figure 2).

KEY REFERENCES1. Neuman Å, Hohmann C, Orsini N,

Pershagen G, Eller E, Kjaer HF, et al. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med 2012;186:1037-1043.

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0

10

20

30

40

50

60

70

80

1 2Age (years)

Atopic (n=94)Non-atopic (n=59)

3 4 5 6 7 8 9 10 11 12 13

Pre

vale

nce

(%)

Asthmarisk

Asthma risk

Asthma risk

FcεR1-enhanced inflammation

Myeloid cells: activation and trafficking

TH2 memory cell trafficking

Bone marrowamplification

Atopic march

Upperrespiratoryinfection

Lowerrespiratoryinfection

Episodicmoderate-intensity

airway inflammation

Perennialaeroallergensensitization Continuous exposure

Persistent low-levelairway inflammation

Infection resistance Local inflammation

Atopic sensitization: prevention and reversal

Antivirals, IE,type 1 IFN

IE, topical IL-4/IL-13Rα antagonist, mAb to IgE, Treg stimulants

SystemicIL-4/IL-13Rαantagonist

Potentialtarget

Potentialtarget

SCIT, SLIT

SCIT,SLIT

Immuno-prophylaxis

Figure 2 Strategies for Asthma Treatment and Prevention. (Reprinted by permission from Macmillan Publishers Ltd: Nat Med, Holt PG, Sly PD, Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment,18, 726-

735, copyright 2012.)

Figure 1 Prevalence of current wheeze from birth to age 13 years in

children with any wheezing episode at school-age (5-7 years), stratified for

atopy. (Reprinted from The Lancet, 368, Illi S, von Mutius E, Lau S, et al, Perennial

allergen sensitisation early in life and chronic asthma in children: a birth cohort

study, 763-770, Copyright 2006, with permission from Elsevier.)

Natural history of asthma

2. Holt PG, Sly PD. Viral infections and atopy in asthma pathogene-sis: new rationales for asthma pre-vention and treatment. Nat Med 2012;18:726-735.

3. Illi S, von Mutius E, Lau S, Nigge-mann B, Grüber C, Wahn U, et al. Perennial allergen sensitisation early in life and chronic asthma in

children: a birth cohort study. Lan-cet 2006;368:763-770.

4. Lau S, Illi S, Sommerfeld C, Nig-gemann B, Bergmann R, von Mu-tius E, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicen-tre Allergy Study Group. Lancet

2000;356:1392-1397.

5. Wahn U, Lau S, Bergmann R, Kulig M, Forster J, Bergmann K, et al. Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 1997;99:763-769.

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Genetics of asthma

• A precise definition of the clinical phenotype and biological endotype is required as a base for genetic investigations

• Asthma is a polygenetic disease with many genes involved in different biological mechanisms

• Identifying genes responsible for the individual differences in response to asthma drugs is essential for improving treatment outcomes

• Gene-gene interactions: different genes interact with each other in the pathogenesis of asthma. While the effect of one single polymorphism may be modest, the combined effect of different genes may be substantial

• Gene-environment interactions: genes interact with environ-mental exposures in determining the risk for asthma

• Epigenetic mechanisms are likely to play a role in the development of asthma and may be activated by environmental exposure

HERITABILITY OF ASTHMAChildren of asthmatic mothers have an odds ratio (OR) of approxi-mately 3 to suffer themselves from asthma. The fathers’ influence is slightly smaller, but still sizeable (OR about 2.5), according to a me-ta-analysis aggregating data from 33 studies. For adult-onset asthma less data are available, but the re-sults point towards the same direc-tion. Thus, hereditary factors clear-ly do play a role in the development of asthma.

During the last one or two decades asthma research has identified an impressive number of the parts of the puzzle: many genes, gene-gene interactions, gene-environment interactions, epigenetic modifica-tions. The next challenge is to as-semble the puzzle in order to see the bigger picture.

GENES ASSOCIATED WITH ASTHMAIn the early days of asthma genet-ics the hope was to find one single gene explaining asthma. Mean-while, using candidate-gene ap-proaches and linkage studies fol-lowed by positional cloning many genes have been linked to asthma; in 2008 over 30 candidate genes have been listed. During the last decade, using whole genome se-

quencing many more genes have been added to the list which keeps growing.

Asthma is a complex disease with several clinical phenotypes and different endotypes, as defined by various biological mechanisms, which, in turn, involve different genes. For example STAT6, a gene encoding a transcription factor in-volved in Th2 cell differentiation has been described to be associ-ated with total serum IgE levels. Atopy is a component of asthma, however, it is neither required nor sufficient to explain asthma; thus,

different variants of the STAT6 gene will only explain a part of the genetic basis of asthma. Polymor-phisms of the ADAM33 gene (A Disintegrin And Metalloprotein-ase gene family-member), to give another example, are associated with diminished lung function and relate to another part of the patho-genesis of asthma.

Genes found to be associated with asthma can be grouped according to different criteria. March et al have proposed several functional categories (Table 1).

GENETICS OF ASTHMA7

Ke y m e ssag e s

Roger Lauener Children’s Hospital of Eastern Switzerland

St. Gallen, Switzerland

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Genetics of asthma

ASTHMA PHARMACOGENETICSOf note in asthma genetics, re-search has also identified genes re-sponsible for individual differences in response to treatment. Polymor-phisms in the β2-adrenoreceptor encoding gene have been implicat-ed in the variable response to treat-ment with β2-adrenoreceptor ago-nists. Other genes such as CRHR1 (corticotrophin-releasing hormone receptor 1) or GLCCI1 (glucocor-ticoid-induced transcript 1 gene) have been suggested to modify responses to corticosteroids. Such observations may pave the way to personalized treatment of asthma, but remain to be confirmed.

GENE-GENE INTERACTIONSIn a given patient not only one gene will determine whether or not the patient will suffer from asthma. Rather, variants of different genes will interact, enhancing or atten-uating each other’s effect on the disease development. As an exam-ple, for the participants in a large German birth cohort study the effect of polymorphisms of IL-4, IL-

13, IL-4RA and STAT 6 each had a modest effect on the children’s risk to suffer from asthma. However, when combined, the asthma risk increased 16.8 fold. This example illustrates the effect of the interac-tion of genes involved in one aspect of asthma pathogenesis, such as regulation of Th2-mediated cell re-sponses. There are, however, many more biological processes involved in the development of asthma, such as inflammatory responses or epi-thelial barrier function, and vari-ants in each of the genes involved in these processes will likely inter-act with other genes leading to or protecting from disease.

GENE-ENVIRONMENT INTERACTIONSFor some asthma risk or protec-tive genes, conflicting results have been described in different studies. One explanation is that the effect of a genetic variant may depend on environmental exposures and vice versa. Well studied examples for this are effects of polymorphisms in the endotoxin receptor CD14 or

TABLE 1

Functional categories of genes associated with asthma

Th2-mediated cell responses GATA3IL-4STAT6IL-13

TBX21IL-4RAIL-12BFcεR1

Inflammation IL-18TNFαLeukotriene C4 synthase

IL-18R1

ALOX-5

Environmental sensing, innate immune receptors for microbes

CD14TLR-4TLR-10HLA class II genes

TRL-2TLR-6NOD1/CARD4

Airway remodeling ADAM33DPP10

COL6A5GPRA

Bronchoconstriction CHRNA3/5NOS1

PDE4D

Epithelial barrier dysfunction Filaggrin (FLG) CC16

DEFB1

Chemokines CCL-5, 11, 24, 26

in the TLR2 genes that depend on the microbial load in the environ-ment. When assessing the effect of a gene on the development of asth-ma one thus always has to consider potentially interacting environ-mental exposures.

EPIGENETICSThe effect of environmental ex-posures has been shown to have long-lasting effects on immune re-sponses related to allergic disease, and even prenatal exposures have the potential to modify the devel-opment of atopic diseases during childhood. Recent data suggest that epigenetic mechanisms such as modifications in methylation of different genes might explain such observations.

KEY REFERENCES1. Lim RH, Kobzik L, Dahl M. Risk

for asthma in offspring of asth-matic mothers versus fathers: a meta-analysis. PLoS One 2010;5:e10134.

2. Ober C, Vercelli D. Gene-envi-ronment interactions in human disease: nuisance or opportunity? Trends Genet 2011;27:107-115.

3. Vercelli D. Discovering suscepti-bility genes for asthma and allergy. Nat Rev Immunol 2008;8:169-182.

4. March ME, Sleiman PM, Hakonar-son H. Genetic polymorphisms and associated susceptibility to asthma. Int J Gen Med 2013;6:253-265.

5. Roduit C, Wohlgensinger J, Frei R, Bitter S, Bieli C, Loeliger S, et al. Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis. J Allergy Clin Immunol 2011;127:179-185.

6. Michel S, Busato F, Genuneit J, Pekkanen J, Dalphin JC, Riedler J, et al. Farm exposure and time trends in early childhood may in-fluence DNA methylation in genes related to asthma and allergy. Al-lergy 2013;68:355-364.

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Pharmacogenetics is the study of the role of genetic determinants in the variable, inter-individual re-sponse to medications (Figure 1). Numerous examples of heritable differences in pharmacokinetics (drug distribution and metabolism) in individuals resulting in varied clinical response to medications have been described. Other mech-anisms underlying the genetic re-sponse to drugs include alterations in pharmacodynamics (changes in the drug target), idiosyncratic as-sociations (unintended side effects in predisposed individuals), and ge-netic predisposition to the disease in which the treatment is to be in-stituted. The two main categories of asthma drugs are commonly referred to as “reliever” drugs that target acute bronchoconstriction and “controller” drugs that reduce the severity of airway inflamma-tion and frequency of obstruction. The main reliever drugs are rap-id-acting β

2-agonists (e.g., albuter-

ol, metaproterenol, pirbuterol, le-valbuterol) that are also referred to as bronchodilators, since they relax the bronchial smooth muscle by activating β

2-adrenergic recep-

tors. This is the treatment of choice for mild intermittent asthma. For mild persistent, moderate, and se-vere asthma, reliever treatment is

Ke y m e ssag e s• Pharmacogenetics is the study of how heredity influences

medication response• There are three major medication classes used in asthma

treatment - short acting beta-agonists, inhaled corticosteroids, and leukotriene modifiers

• As many as one-half of all patients do not respond to one or more of the classes of asthma medications, supporting a role for pharmacogenetics

• Familial studies have demonstrated a genetic component to corticosteroid and beta-agonist medication response

• Pharmacogenetic studies have identified genetic variants associated with response to each asthma medication class

• The future of asthma pharmacogenetics lies in personalized therapy for a given patient

Scott T. Weiss Kelan Tantisira Harvard Medical School

Boston, USA

PHARMACOGENETICS OF ASTHMA8

usually combined with controller treatment, such as inhaled corti-costeroids (ICS) and the leukot-riene modifiers. ICS (e.g., budeso-nide, beclomethasone, flunisolide, and fluticasone) and leukotriene modifiers (e.g. montelukast and zileuton) target the inflammatory micro-environment of the airway to reduce airway obstruction and hyper-responsiveness.

It has been estimated that as many as one-half of asthmatic patients do not respond to treatment with β

2-agonists, leukotriene antago-

nists, or inhaled corticosteroids

(Figure 2), suggesting a potential role for pharmacogenetics in de-fining treatment response. Fam-ily and twin studies have demon-strated that endogenous levels and exogenous administration of glucocorticoids, as well as bron-chodilator response are heritable and hence genetic in origin. Phar-macogenetics began by looking at candidate pathway genes and drug treatment response. Prior to 2004, genetic variants in five genes had been associated with altered ther-apeutic response to four classes of asthma drugs: the β

2-adrener-

gic receptor (ADRB2) for the beta

Pharmacogenetics of asthma

26


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agonist pathway, 5-lipoxygenase (ALOX5) and leukotriene C4 syn-thase (LTC4S) for the leukotriene pathway, corticotropin releasing factor receptor type 1 (CRHR1) for the steroid pathway, and cy-tochrome p450 1A2 (CYP1A2) for the methylxanthine (e.g. theophyl-line, which is no longer first line therapy for asthma) pathway. Since 2004, additional novel replicated

candidate genes for various ster-oid response phenotypes (STIP1, TBX21, DUSP1, and FCER2) (Fig-ure 3) and beta-agonist response phenotypes (AC9, CRHR2, ARG1, and GPCR5) have been published. Most recently, investigators have used genome-wide association studies (GWAS) where drug re-sponse phenotypes are related to single nucleotide polymorphisms

across the genome in a genomic approach to Identify novel genes. Tantisira and coworkers utilized this approach to identify a func-tional polymorphism in the pro-motor region of GLCCI1 as a pre-dictor of change in lung function in response to inhaled corticosteroid and were able to replicate this find-ing in several other asthma popula-tions (Figure 4). Two other asthma

Figure 1 Pharmacogenetics is the study of genetic influences on the response to medications. The overarching goal of pharmacogenetics is the personalized prediction of who will respond to medications in a safe and effective fashion.

Figure 2 Population response to inhaled corticosteroids (A) and short acting beta-agonists (B). For both medications, there is wide inter-individual variability in response that is consistent across multiple populations; both good and poor responders

can be readilty identified. (A reproduced from Tantisira KG, Lake S, Silverman ES, et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol

Genet 2004;13:1353-1359 with permission from Oxford University Press; B reprinted by permission from Macmillan Publishers Ltd: Pharmacogenomics Journal, Tse SM, Tantisira K, Weiss ST. The pharmacogenetics and pharmacogenomics of asthma therapy.

Pharmacogenomics J 2011;11:383-392, copyright 2011.)


Genotype 1

Complete without adverse events

Incomplete without adverse events

Incomplete with adverse events

No response without adverse events

No response with adverse events

Identical phenotype

Response to treatment

Genotype 2 Genotype 3 Genotype 4 Genotype 5

Best scenario Worse scenario

Bronchodilator response (%) in ACRN, CARE and CAMP

B30

25

20

15

10

5

0

less

th

an 1

0-1

0 to

-5

-5 to

0

0 to

5

5 to

10

10 to

15

15 to

20

20 to

25

25 to

30

30 to

35

35 to

40

grea

ter

than

40

ACRNCAMPCARE

Per

cent

of s

ubje

cts

(%)

A40

25

20

15

10

5

0

30

35

Pat

ient

s, %

Adult StudyCAMPACRN

> 4030 to 40

20 to 30

10 to 20

0 to 10

-10 to 0

-20 to -10

< -20

% Change in FEV1 from Baseline

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pharmacogenetic GWAS genes have been reported: SPATS2L for acute short acting beta-agonist re-sponse and the T gene for inhaled corticosteroid response. Recent trends in the field have been to aid in the identification of individual genes by GWAS to identifying reg-ulatory variants via the expression quantitative trait locus approach (eQTLs) using human immortalized cell lines treated with the drug of interest, as well as to move away from individual genes toward a sys-tems approach of identifying bio-logically interacting genes through

the aid of computational networks aimed at predicting drug treatment response. The overarching goal of these studies is to eventually iden-tify a set of genetic variants that together will allow the personal-ized prescription of asthma thera-pies that will avoid side effects and optimize therapeutic response.

KEY REFERENCES1. Weinshilboum R. Inheritance

and drug response. N Engl J Med 2003;348:529-537.

2. Evans WE, McLeod HL. Pharma-cogenomics--drug disposition,

drug targets, and side effects. N Engl J Med 2003;348:538-549.

3. Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeutic responses in asthma. Br Med Bull 2000;56:1054-1070.

4. Tse SM, Tantisira K, Weiss ST. The pharmacogenetics and pharmacog-enomics of asthma therapy. Pharma-cogenomics J 2011;11:383-392.

5. Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011;365:1173-1183.

Cha

nge

in F

EV 1

(% o

f pre

dict

ed)

16

12

14

10

8

4

2

6

0CT TTCC

SS Adultstudy

LOCCS CARE Figure 4 Association of a variant (rs37973, where the C allele is common and the T allele

is rarer) in the GLCCI1 gene with reduced lung function response to inhaled corticosteroids

in four independent populations. The variant was identified through genome-wide association testing. (From N Engl J

Med, Tantisira KG, Lasky-Su J, Harada M, et al, Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma,

365, 1173-83, Copyright 2011 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.)

Figure 3 Association of a genetic variant in the FCεR2 (low affinity IgE gene) with risk of subsequent asthma exacerbations (emergency room visits or hospitalizations) while on inhaled corticosteroids, which generally are protective against

exacerbations. The variant has no effect on those not taking the medication. However, in both Caucasians and African Americans, subjects with two copies of the genetic variant in their DNA were 3-4 times as likely to have an exacerbation

compared to those with zero to one copy of the variant. (Reprinted from J Allergy Clin Immunol, 120/6, Tantisira KG, Silverman ES, Mariani TJ, et al, FCER2: a pharmacogenetic basis for severe exacerbations in children with asthma, 1285-1291, Copyright

2007, with permission from Elsevier.)

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Allergic inflammation can lead to several diseases, including asth-ma, allergic rhinoconjunctivitis, anaphylaxis, urticaria and atopic dermatitis, which are all complex disorders with several disease variants caused by different un-derlying cellular and molecular mechanisms. Our understanding of asthma mechanisms are emerg-ing from direct analyses of human biopsies, bronchoalveolar lavage, sputum, peripheral blood cells and serum, clinical response to drugs and biologicals that target a specific molecular mechanism. The mouse model of allergic lung inflamma-tion has similarities with human Th2 and eosinophilic inflammation, but drugs which suppress allergic inflammation in this model have failed in clinical trials in humans. Asthmatic airway inflammation through the infiltration of cells and release of potent inflammatory mediators and remodeling of the airway wall represent the essen-tials of the disease pathogenesis. Asthmatic bronchial wall shows al-tered wound repair response with secretion of growth factors that induce remodeling during chronic inflammation. Remodeling involves almost all elements of the airway wall and occurs throughout the bronchial tree. It is characterized

by smooth muscle hypertrophy, goblet cell hyperplasia, subepithe-lial basement membrane thicken-ing and angiogenesis. Airway re-modeling increases the thickness of the airway wall and leads to ir-reversible airflow obstruction and airway hyperresponsiveness, and is associated with increased dis-ease severity.

The recently identified innate type-2 immune effector leukocyte, the nuocyte, provides a missing

link between the innate and adap-tive Th2 response for the recruit-ment of T cells and eosinophils. During initial allergen sensitization of the airways, Th2 lymphocyte differentiation from naive T cells takes place and requires IL-4 to activate the transcription factors signal transducer and activator of transcription 6 (STAT6) and GA-TA-binding protein 3 (GATA3). In-duced sputum from asthmatic air-ways and peripheral blood contain increased numbers of both plasmo-

Ke y m e ssag e s• Asthma is a heterogeneous disease consisting of multiple different

pathogenetic subgroups with different cellular and molecular characteristics

• Th2-like immune response and peripheral blood and lung eosinophilia represent a consistent and dominant subgroup

• Molecular and cellular mechanisms of non-Th2 associated asthma are poorly defined

• Allergy and IgE play a role in the pathogenesis of a majority of pediatric and approximately half of adult patients

• Remodeling characterized by smooth muscle hypertrophy, goblet cell hyperplasia, subepithelial basement membrane thickening and angiogenesis is a key pathogenetic feature

• Recent studies have demonstrated an essential role of permissive bronchial epithelial tight junctions and leaky epithelium

• Small molecule mediators such as leukotrienes, adenosine, ATP that affect cellular chemotaxis, smooth muscle relaxation and tissue inflammation play roles

Mübeccel Akdis Swiss Institute of Allergy and Asthma Research

Davos, Switzerland

THE PATHOGENESIS OF ASTHMA9

The pathogenesis of asthma

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Figure 1 Pathogenic mechanisms in asthma. Epithelial leakiness and activation and their proinflammatory cytokines and chemokine production that induces inflammation and contributes to Th2 response: TNF-α, IL-13, TSLP, IL-31, IL-33.

Highly activated epithelial cells undergo apoptosis and shedding takes place. Cell migration and chemokines are essential players for the recruitment of inflammatory cells, which is followed by survival and reactivation of migrating inflammatory

cells and their interaction with resident tissue cells and other inflammatory cells. Innate lymphoid cells (ILC2) play a role on T and B cell activation and recruitment and are early providers of Th2 cytokines and T cell recruitment. Th2 type of an

immune environment is characterized by IL-4, IL-5, IL-9, IL-13, IL-25, IL-33 production coming from Th2 cells and tissue cells. Eosinophilia is induced by IL-5, IL-25, IL-33. Local and systemic IgE production takes place in allergic patients with the involvement of IL-4, IL-13. Other effector T cell subsets, such as Th9, Th17 and Th22 cells also play partial roles in

inflammation, mucus production, tissue healing. Smooth muscle, myofibroblasts activation and bronchial hyperreactivity is related to IL-4, IL-9, IL-13, IL-25, IL-33. Several chemokines, and arachidonic acid pathway molecules and other small

molecules play roles in the inflammatory cell recruitment and further augmentation of the inflammatory cascades. (Modified from Papadopoulos NG, Agache I, Bavbek S, et al. Research needs in allergy: an EAACI position paper, in collaboration with EFA. Clin

Transl Allergy. 2012;2:21)

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cytoid and myeloid dendritic cells, which further increase in number upon allergen challenge. Myeloid dendritic cells represent an inflam-matory subset of dendritic cells in the asthmatic lungs, whereas sev-eral studies have shown a role of plasmocytoid dendritic cells tar-geted more towards the humoral immune response, suppression of lung inflammation as well as aller-gen tolerance. Th2 cytokines such as IL-4, IL-13 play a role in IgE syn-thesis and IL-5, IL-25 and IL-33 in-duce airway eosinophilia in animal models of asthma. IL-9 expression is also increased markedly in re-sponse to allergen challenge. In studies using IL-9 transgenic and knockout mice, direct IL-9 instil-lation into the lungs and blocking monoclonal antibodies, it has been shown that IL-9 drives mucus pro-duction, both by a direct effect on airway epithelia and also by inter-acting with IL-13. Th17 cells are a distinct T cell lineage suggested to be involved in asthma and corti-costeroid insensitivity. In humans, a subset of Th2 and Th17 memory and effector cells, producing Th17 and Th2 cytokines at the same time may be more important com-pared to single Th2 cells. The role of regulatory T cells in suppression of allergic inflammation has been shown in allergen-immunotherapy and high dose allergen exposure models such as cat owners with asthma. Recently, an IL-10 secret-ing regulatory B cell subset joined the family of regulatory cells that play a role in allergen tolerance and IgG4 production.

Eosinophilic asthma is a distinct phenotype of asthma that is asso-ciated pathologically with thick-ening of the basement membrane and pharmacologically with corti-costeroid responsiveness. In con-trast, neutrophilic asthma includes

patients with severe disease, and appears to be relatively corticos-teroid resistant. Neutrophils ac-cumulate in the airway in more severe forms of asthma, and neu-trophil numbers are associated with chronic airway narrowing. In addition, neutrophils are promi-nent during acute severe asthma exacerbations, suggesting roles for both the initiation and resolution of attacks. Current knowledge on the mechanisms of neutrophilia in asthma, and clinical consequences of decreasing airway neutrophilia is very limited.

The asthmatic epithelium is intrin-sically defective in its physical bar-rier function with incomplete for-mation of tight junctions, thereby facilitating penetration of inhaled allergens into the airway tissue. Related to this defect, a proportion of the asthma-related allergens have intrinsic biological proper-ties that increase their capacity to penetrate the epithelial barrier and trigger an inflammatory sig-nal in submucosal cells and tissues. Beyond proteolytic allergens, ad-ditional environmental stimuli such as respiratory viruses and air pollutants also disrupt tight junc-tions and impair barrier function in addition to activation of a whole inflammatory cascade leading to early development and exacerba-tions of asthma. TSLP, IL-33 and IL-25 are generated by the airway epithelium in response to activa-tion of pattern recognition recep-tors such as Toll-like receptors or following cytotoxic epithelial inju-ry. These three epithelial cytokines have the potential to bridge innate and adaptive immunity to sustain the Th2 response toward a more chronic state that is characteristic of asthma. Intensive research in the area is essential to fully uncov-er the molecular pathways of in-

flammation and link pathogenesis to clinical phenotypes to find bet-ter treatments.

KEY REFERENCES1. Agache I, Akdis C, Jutel M, Vir-

chow JC. Untangling asthma phe-notypes and endotypes. Allergy 2012;67:835-846.

2. Holgate ST. The sentinel role of the airway epithelium in asth-ma pathogenesis. Immunol Rev 2011;242:205-219.

3. Akdis CA. Therapies for allergic inflammation: refining strate-gies to induce tolerance. Nat Med 2012;18:736-749.

4. Kast JI, Wanke K, Soyka MB, Wawrzyniak P, Akdis D, Kingo K, et al. The broad spectrum of interepithelial junctions in skin and lung. J Allergy Clin Immunol 2012;130:544-547.

5. Nembrini C, Marsland BJ, Kopf M. IL-17–producing T cells in lung im-munity and inflammation. J Allergy Clin Immunol 2009;123:986-994.

6. Fahy JV. Eosinophilic and Neu-trophilic Inflammation in Asthma. Proceedings of the American Thorac-ic Society 2009;6:256-259.

6. Fitzpatrick AM, Baena-Cagnani CE, Bacharier LB. Severe asthma in childhood: recent advances in phenotyping and pathogenesis. Curr Opin Allergy Clin Immunol 2012;12:193-201.

7. Meyer N, Christoph J, Makrin-ioti H, Indermitte P, Rhyner C, Soyka M, et al. Inhibition of angi-ogenesis by IL-32: possible role in asthma. J Allergy Clin Immunol 2012;129:964-973.

8. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Ak-dis DG. IgG4 production is con-fined to human IL-10-producing regulatory B cells that suppress antigen-specific immune re-sponses. J Allergy Clin Immunol 2013;131:1204-1212.


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Asthma is a chronic inflammato-ry disease of the airways that in-volves multiple pathophysiological mechanisms leading to recurrent attacks of bronchial narrowing and to structural alterations of the bronchi (Figure 1). In the major-ity of patients the primary cause of inflammation is sensitization to airborne allergens such as plant pollens, dust mites or pet danders. In genetically predisposed individ-uals, these allergens are taken up by dendritic cells in the airways, processed and presented to T lym-phocytes. This triggers the immune response of the so-called Th2 type with production of specific cy-tokines such as IL-4, IL-5, IL-13 by T lymphocytes (Figure 2). Th2 type cytokines promote the formation of specific antibodies of the IgE class that are subsequently fixed on the surface of mast cells and ba-sophils. Mast cells, which are very abundant in the airways, and ba-sophils, which are recruited in the bronchial mucosa from the blood, are subjected to rapid and massive activation after inhaled allergens crosslink their surface IgE. Degran-ulation of mast cells and basophils results in the release of very potent mediators of bronchoconstriction such as histamine, cysteinyl leukot-rienes, prostaglandins and plate-

let-activating factor (Figure 3). Within minutes after allergen in-halation these mediators induce a strong constriction of the airways, generate edema of the airway walls and enhance the production of mucus. In addition to these acute responses, cytokines produced by both Th2 lymphocytes and by mast cells and basophils induce the re-cruitment of eosinophils from the blood into the airways. Infiltra-tion of eosinophils in the bronchi-al mucosa is a hallmark of allergic asthma and it persists even when symptoms of asthma are not pres-ent. While these are considered

the early mechanisms of allergic asthma in the majority of asthmat-ics, some other mechanisms that promote airway inflammation in specific subsets of patients are also activated.

Viral or bacterial infections can contribute to the development of asthma by activating cells of the in-nate immunity such as macrophag-es or natural killer (NK) cells. Spe-cific subtypes of T lymphocytes, namely Th1 and Th17 are increas-ingly recognized in chronic phase of asthma. Th17 cells are mainly in-volved in the defense against infec-tious agents but they are also acti-

Ke y m e ssag e s• Asthma is characterized by persistent chronic inflammation and

remodeling of the airways• Airway inflammation is initiated by a dysregulated immune

response to inhaled allergens• Several inflammatory effector cells contribute to development of

asthma including mast cells, eosinophils, basophils, macrophages, T lymphocytes as well as airway epithelial cells and smooth muscle cells

• Mediators produced by inflammatory cells induce acute constriction of the bronchi, airway edema, increased mucus production as well as epithelial damage and smooth muscle proliferation

• Chronic inflammation and structural remodeling of the airways are responsible for progressive deterioration of lung function

THE UNDERLYING MECHANISMS OF ASTHMA10

Massimo Triggiani University of Salerno

Italy

Marek Jutel Wroclaw Medical University, Poland

Edward F. Knol University Medical Center Utrecht, The Netherlands

The underlying mechanisms of asthma

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Figure 1 Pathogenic mechanisms of asthma. In genetically predisposed individuals environmental factors such as allergens, infections or irritants may induce epithelial damage that leads to a dysregulated immune response. Several cells

including T lymphocytes (Th2 cells), mast cells (MC), eosinophils (Eos), basophils (Baso) and macrophages (Mf) are activated in the airways of asthmatics and secrete mediators responsible for persisting inflammation, bronchoconstriction and airway

remodeling.

Figure 2 The complex network of immune response in asthma. T lymphocytes are the key players in asthmatic inflammation, orchestrating adaptive and innate immunity and triggering airway structural remodelling. ILC2: innate

lymphoid cells type 2. (Adapted from Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. J Allergy Clin Immunol 2011;128:451-462).

Viruses, Bacteria, Pollens, Allergens, Superallergens, Air Pollution

} Environmental Triggers

Intact epitheliumIntact epithelium

Angiogenesis

Airway smooth muscle mast cell

myositis

Tissue remodeling

Myofibroblast activation

Increased smooth muscle mass

Asthma Symptoms

Airway hyperresponsiveness Airway narrowing

Increased releasability

Damaged epithelium

Injury Repair

Genes

MC Eos Baso

Mf Th2

Chronic allergic

inflammation

Chemokines Cytokines

Growth Factors

NeuIL-17AIL-17FIL-22

Th17

Th

Th1

Th2

Th9

Eos

IFN γ TNF α

IFN γ TNF α

IL-5

PGD2

IL-4IL-9

IL-13

ILC2

Epitheliuminjury

EpitheliumAngiogenesis

Angiogenesis

MC

VEGF

IL-9IL-9

IL-4IL-13

TGF β

Fibrocytedifferentiation

Baso

VEGF

Eos

IL-3IL-5

GM-CSFIL-3

IL-13IL-4

B cell

IgEYYY

Smooth muscle layer remodeling


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vated in patients with asthma and produce specific cytokines that trigger the recruitment of neutro-phils to the bronchial mucosa in se-vere forms of asthma.

In addition, the airway epithelium is not only important as a physical barrier, but can also respond to innate-type signals by releasing Th2-inducing cytokines, such as TSLP and potent pro-inflammatory cytokines such as TNFα. Chronic injury of the airway epithelium re-sults in increased permeability of inhaled antigens, as well as induc-es reactivation of the epithelial–mesenchymal trophic unit (EMTU) formed by the epithelium and the underlying fibroblast sheath. The airway smooth muscle cells seem to be another important player by expressing numerous adhesion molecules, cytokine and chemok-

ine receptors, as well as by releas-ing cytokines to the local environ-ment.

Persistent inflammation in the airways and the ongoing struc-tural remodeling of the airways is responsible for the bronchial hy-perreactivity to both specific (al-lergen) and non-specific (irritants, histamine, metacholine) stimuli. The main features of remodeling in asthma are an increased thickness of the membrane below the sur-face epithelium of the bronchi, the growth in the size and number of mucous glands, an increase in the muscle layer of the bronchi and an abnormal formation of new blood vessels. All these changes deter-mine further increase in the airway resistance and contribute to the worsening of lung function that can be observed in chronic asthma.

KEY REFERENCES1. Holgate ST. Innate and adaptive

immune responses in asthma. Nat Med 2012;18:673-683.

2. Holgate ST. Pathogenesis of asth-ma. Clin Exp Allergy 2008;38:872-897.

3. Galli SJ, Tsai M. IgE and mast cells in allergic diseases. Nat Med 2012;18:693-704.

4. Agache I, Akdis C, Jutel M, Vir-chow JC. Untangling asthma phe-notypes and endotypes. Allergy 2012;67:835-846.

5. Koziol-White CJ, Panettieri RA Jr. Airway smooth muscle and immu-nomodulation in acute exacerba-tions of air way disease. Immunol Rev 2011;242:178-185.

6. Marone G, Triggiani M, Genovese A, De Paulis A. Role of human mast cells and basophils in bronchial asthma. Adv Immunol 2005;88:97-160.

Figure 3 Central role of lung mast cells and basophils in bronchial asthma. (Reprinted from Trends Immunol 26/1, Marone G, Triggiani M, de Paulis A, Mast cells and basophils: friends as well as foes in bronchial asthma?, 25-31, Copyright 2005, with

permission from Elsevier.)

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Asthma is defined as reversible airflow limitation (or bronchial hyperresponsiveness) associated with a spectrum of related clinical symptoms. However, it is increas-ingly recognized that the underly-ing pathobiologic pathways leading to this integration of clinical and physiologic changes are diverse. While this concept of asthma het-erogeneity has been around for years, increases in pathobiologic (particularly genomic) samples, the use of unbiased statistical cluster-ing approaches and the emergence of targeted molecular-based thera-pies have rapidly advanced the con-cept. Inherent in these approaches is the recognition that phenotypes of asthma exist. A phenotype is defined as the characteristics of a patient which result from the inter-action of genetic background with environmental influences (Figure 1). Examples include early onset al-lergic asthma and obesity-related asthma. However, efforts are now being made to identify asthma en-dotypes. An “endotype” is generally defined as the integration of a spe-cific identifiable underlying patho-biologic process, the inhibition of which contributes critically to elemental clinical characteristics. While no widely agreed criteria upon endotypes are yet described,

progress has been made.

Phenotyping began to move closer to endotyping with the observa-tion that only a portion of “clinical asthma” was associated with an underlying Th2-like immuno-in-flammatory process. This “Th2-like” (eosinophilic) molecular phe-notype is present in about 50% of adult asthma, from mild to severe. This Th2 “molecular phenotype” encompasses some but not all pa-tients with traditional “allergic asthma”, as well as some patients with exercise-induced asthma. Im-portantly, it also includes a group

with adult onset, highly eosinophil-ic asthma. Patients with a Th2-like molecular phenotype have a range of corticosteroid (CS) sensitivity, confirming the overall heterogene-ity of even this molecularly defined phenotype. Biomarkers, including blood eosinophils, periostin and exhaled nitric oxide (NO) can be used to identify this Th2-like phe-notype. In fact, using these Th2-like biomarkers improves the abil-ity to identify responders to Th2 targeted therapies and improve outcomes. However, responses still vary, even in Th2-like patients. Thus, it is likely that some Th2-like

Ke y m e ssag e s• Asthma is a heterogeneous “disease” consisting of multiple

different subgroups• A phenotype is identified by the integration of characteristics

arising from the interaction of the patient’s genes with the environment

• Molecular phenotypes incorporate pathobiologic characteristics and biomarkers

• An endotype can only be fully defined when inhibition of a specific molecular pathway leads to improvement in clinical outcomes

• Th2-like molecular phenotypes are beginning to be identified which encompass both consistent clinical characteristics, biomarkers and even specific molecular pathways

• Non-Th2 associated phenotypes of asthma remain more poorly defined

PHENOTYPES & ENDOTYPES: EMERGING CONCEPTS ON ASTHMA HETEROGENEITY

11Sally Wenzel

University of Pittsburgh USA

Phenotypes & endotypes: emerging concepts on asthma heterogeneity

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Phenotypes & endotypes: emerging concepts on asthma heterogeneity

Figure 2 Potential Th2-associated endotypes.

molecular phenotypes (eventually endotypes) will respond better to interleukin-4/-13 directed therapy while another group will respond better to an interleukin-5 direct-ed therapy (Figure 2). Studies that link these molecular targeted ther-apies to improvements in specific characteristics, pathobiology and biomarkers will ultimately identify asthma endotypes.

The other broad asthma pheno-type includes patients who exhibit no evidence of Th2 inflammation.

This “non-Th2” associated asth-ma generally is defined by the ab-sence of biomarkers associated with Th2-like asthma and consists of a poorly defined mix of obesity associated asthma, neutrophilic asthma, paucigranulocytic asthma and smoking associated asthma, all of whom are generally poorly CS responsive. These patients may be less severe in general, with clinical trials suggesting Th2-like asthma is more likely to exacerbate. While there are few definitive studies of what is driving non-Th2 asthma, it

Figure 1 The progression of phenotypes to endotypes.

Molecular phenotypes

Incorporation into clinical phenotype of associated

pathobiologic processes, ideally at molecular level

Endotypes

Confirmation through molecular targeting that identifiable molecular pathway

contribute to the clinical characteristics associated with molecular phenotypes

Overlapping clinical,

physiologic,and hereditarycharacteristics

Phenotypes

Exercise induced bronchospasm

Mild disease, mast cell associated, IL-9 responsive

Mild, early onset allergic asthmaHereditary, CS responsive and

IL4/-13 responsive

Severe early onset allergic asthma

Hereditary, poorly CS responsive but

IL-4/13 responsive

Late onset eosinophilic asthmaNasal polyps, aspirin

sensitivity, IL-5 responsiveIn

crea

sin

g s

ever

ity

is likely that neurogenic, oxidative stress and alternative innate or adaptive immune pathways are, playing a role. Interestingly recent studies strongly support the pres-ence of a later onset, obese asthma phenotype, which lacks any Th2-like immune processes and which may be identified through altera-tions in the natural inhibitor of in-ducible NO synthase, asymmetric dimethylarginine in blood. Studies are ongoing to determine whether interventions in this pathway will improve clinical asthma outcomes. Future studies, which integrate clinical and molecular data, espe-cially when done with a targeted intervention, in large numbers of patients will greatly refine our abil-ity to define phenotypes and even endotypes of asthma.

KEY REFERENCES1. Corren J, Lemanske RF, Hanania

NA, Korenblat PE, Parsey MV, Ar-ron JR, et al. Lebrikizumab treat-ment in adults with asthma. N Engl J Med 2011;365:1088-1098.

2. Haldar P, Brightling CE, Har-gadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eo-sinophilic asthma. N Engl J Med 2009;360:973-984.

3. Holguin F, Comhair SA, Hazen SL, Powers RW, Khatri SS, Bleecker ER, et al. An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset pheno-type. Am J Respir Crit Care Med 2013;187:153-159.

4. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716-725.

5. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2-driven inflamma-tion defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388-395.

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ENVIRONMENTAL FACTORS AS TRIGGERS OF ASTHMA SYMPTOMS Typical indoor air pollutants that can trigger asthma symptoms in-clude biologic aeroallergens (house dust mites, cockroaches, animal dander, molds, etc.), environmen-tal tobacco smoke (ETS), irritant chemicals and fumes and products from combustion devices (Figure 1), with severity of symptoms var-ying with the level of exposure. So far controlled data are still lacking on the effect of reduction of aller-gen exposure (house-dust mites) in the improvement of pulmonary function tests (PFTs) and reduc-tion in airway inflammation and hyper-responsiveness. Successful allergen avoidance necessitates a comprehensive approach including education, regular cleaning and use of physical barriers, which poses a major problem for disadvantaged social classes.

Typical outdoor pollutants that can trigger and exacerbate asth-ma include pollen, mold spores and air pollutants (Figure 1). In the last decades, high levels of out-door chemical air pollution have been associated with short-term increases in asthma morbidity and mortality. Other hazardous air pol-

lutants, as well as industrial releas-es of volatile organic compounds metals, isocyanates, have been shown to cause and trigger asthma. Of note, most studies provide evi-dence that other precipitating fac-tors, such as viruses, can increase the risk of asthma exacerbations via interactions with allergens. Overall, avoiding environmental allergens and irritants should be one of the primary goals of good asthma management. In addition, clinicians should be aware of the common air pollutants that may af-fect asthmatic patients.

Extreme weather conditions and changing climate may also be an asthma trigger in certain people. Extreme cold, hot, humidity, baro-metric pressure, thunderstorm or strong winds may trigger asthma symptoms in some people (Figure

1 and 2). Moreover, climate factors influence wind patterns, amount and intensity of precipitation and temperature and, thus, severity and frequency of air pollution epi-sodes. Lastly, living in areas where forest fires are common during the summer months or where temper-ature inversion happens during the winter months may also trig-ger asthma symptoms as a conse-quence of poor air quality.

ENVIRONMENTAL FACTORS AND ASTHMA ONSET Sensitization to indoor allergens and outdoor molds and pollen is a risk factor for the development of allergic asthma. Urban air pollution has been implicated as one of the factors responsible for the dramat-ic increase in asthma incidence in recent years. Regarding the onset of asthma, the evidence for causali-

Ke y m e ssag e s• Exposure to indoor and outdoor allergens contributes to asthma

development, aggravations and exacerbations• The irritant effects of environmental tobacco smoke and other

indoor and outdoor air pollutants contribute significantly to asthma morbidity

• Climate change and extreme weather conditions impact on asthma directly and indirectly

ENVIRONMENTAL RISK FACTORS FOR ASTHMA 12

Isabella Annesi-Maesano National Institute of Health and Medical Research

Paris, France

Environmental risk factors for asthma

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Figure 1 Environmental triggers for asthma. (From http://www.astmalergic.ro/images/triggers.jpg, accessed May 20, 2013.)

ty has grown significantly, but it re-mains difficult to separate allergic from non-allergic asthma. Studies showed that children living near heavy traffick have significantly higher rates of wheezing and diag-nosed asthma. Allergic individuals are at higher risk of the effects of the chemicals. The effect seems to

be modified by co-exposures of al-lergens as well as genetic variants, particularly those moderating re-sponse to oxidative stress.

Climate change might affect asth-ma prevalence through an effect on aeroallergens and chemical air pollutants. Any longer-term

change affects pollen and spore production and other phenological events and, at the same time, im-pacts various aerobiological pro-cesses (emission, dispersion and/or transport and deposition of aeroal-lergens). Moreover, climate change can affect anthropogenic emissions (e.g., increase in energy demand for

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Figure 2 Thunderstorm (left) and microscope image of grass pollens (right). Moisture in the air in the initial phase of a thunderstorm causes the airborne pollen granules to rupture in to particles small enough to be breathed deep in to the smaller airways within the lungs. Here, they can irritate the lining to cause inflammation and mucus production which

obstructs airflow leading to asthma attacks. (Grass pollen reproduced with permission of NDT-Educational from http://www.ndt-educational.org/images/artefatti28.jpg, accessed May 20, 2013.)

space cooling, heating) and induces an increase in secondary pollutants (i.e., ozone and particulate matter), thus increasing the risk of asthma development.

UNMET NEEDSExcept for aeroallergens, clear-ly involved in allergic asthma, the distinction between allergic and non-allergic asthma phenotypes has rarely been made when inves-tigating environmental risk factors for asthma. This separation can be of importance for asthma manage-ment, treatment and prevention.

Educational programs for health care professionals and patients often fail to fully incorporate en-vironmental and exposure history. For example, although over half of practicing pediatricians surveyed

in the US see patients with health issues related to environmental ex-posures, fewer than 1/5 are trained in taking an environmental history.

KEY REFERENCES1. Hulin M, Simoni M, Viegi G, Ann-

esi-Maesano I. Respiratory health and indoor air pollutants based on quantitative exposure assess-ments. Eur Respir J 2012;40:1033-1045.

2. Peden D, Reed CE. Environmental and occupational allergies. J Aller-gy Clin Immunol 2010;125:S150-160.

3. Craig TJ. Aeroallergen sensitiza-tion in asthma: prevalence and correlation with severity. Allergy Asthma Proc 2010;31:96-102.

4. Cecchi L, D’Amato G, Ayres JG, Galan C, Forastiere F, Forsberg B, et al. Projections of the effects of climate change on allergic asthma:

the contribution of aerobiology. Allergy 2010;65:1073-1081.

5. Weinmayr G, Romeo E, De Sario M, Weiland SK, Forastiere F. Short-term effects of PM10 and NO2 on respiratory health among children with asthma or asthma-like symp-toms: a systematic review and me-ta-analysis. Environ Health Perspect 2010;118:449-457.

6. Ayres JG, Forsberg B, Annesi-Mae-sano I, Dey R, Ebi KL, Helms PJ, et al. Climate change and respirato-ry disease: European Respiratory Society position statement. Eur Respir J 2009;34:295-302.

7. Salvi S. Pollution and allergic air-ways disease. Curr Opin Allergy Clin Immunol 2001;1:35-41.

8. Carlsten C, Melén E. Air pollution, genetics, and allergy: an update. Curr Opin Allergy Clin Immunol 2012;12:455-460.


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The occurrence of asthma is strongly influenced by environ-mental factors. It has been shown that populations with very similar genetic background differ in the prevalence of asthma depending on the area of residence. For ex-ample, childhood asthma is almost non-existing in rural areas in China, whereas in regions approximately 200 km away, in the capital of Be-jing, the prevalence rises up to 5 percent. Such strong protection is also seen in Karelia which has been divided by the Iron Curtain after World War II into a Finnish and a Russian part. On the Russian side life style has been maintained as in former times, whereas people on the Finnish side have adopted a more westernized lifestyle. The prevalence of asthma in Russian Karelia is very low. In comparison asthma rates in Finnish Karelia are about 5.5 times higher (Figure 1). In Alpine regions protection is seen within rural areas, i.e. among children being raised on traditional dairy farms (Figure 2) as compared to their peers living in the same vil-lage but not living on a farm. Both in the Karelian studies and the farm studies microbial exposures in the environment have been found to explain some of this protective ef-fect on asthma and atopy. The pro-

tection is not mediated by just one particularly potent protective mi-crobe, but by a cocktail of microbi-al exposures, including exposures to certain Gram negative and Gram positive bacteria and fungi (Figure 3). It seems important that children get exposed early in life as this is the time when immune responses and lung tissues mature. The effect of exposures to traditional farms and Karelian environments is sus-tained until adulthood.

In turn, the use of antibiotics and antipyretics is still being debated. Some associations may be attrib-utable to the indication. In other words asthmatics are more likely to use antibiotics and antipyret-ics because of their disease rather than these drugs causing the onset of disease. There is no indication

that vaccinations may increase the risk for asthma.

There are however other signifi-cant risk factors for asthma. The most important is active smoking, particularly by the mother expos-ing her unborn child in utero or of adolescents and young adults. Not only does the risk of asthma increase, but also remission which occurs in a significant proportion of adolescent asthmatics is jeop-ardized by active smoking. Passive smoking also increases the asthma risk. The introduction of the smok-ing ban in Scotland has resulted in significantly reduced rates of asth-ma admissions to hospitals sup-porting such public health meas-ures (Figure 4). Pollution by car and truck traffic exhausts has also been implicated as risk factor, particular-

Ke y m e ssag e s• The occurrence of asthma is strongly influenced by environmental

factors• Exposure early in life to microbes from the environment can

explain some of the protective effect on asthma and atopy• Other significant risk factors for asthma are active and passive

smoking, pollution, indoor moulds and dampness, weight gain or obesity

• Nutrition may also be a source of risk or protective factors

LIFE STYLE RISK AND PROTECTIVE FACTORS FOR

ASTHMA13

Erika von Mutius Ludwig Maximilian University

Munich, Germany

Life style risk and protective factors for asthma

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ly for highly exposed children, i.e. those living 100 – 500 m away from busy motorways. Indoor factors also play a role. Most consistently indoor moulds and dampness have been shown to increase the risk for asthma. It remains unknown which factors account for the risk associ-ated with such moisture damage.

Lifestyle factors are furthermore important. Weight gain and obe-sity have been related to asthma like symptoms and weight loss has

been shown to improve symptoms among asthmatic patients. There-fore, nutrition may also be a source of risk factors, but data collected so far have not identified certain foods as particularly asthmagenic.

KEY REFERENCES1. Pakarinen J, Hyvärinen A, Salkino-

ja-Salonen M, Laitinen S, Nevalain-en A, Mäkelä MJ, et al. Predomi-nance of Gram-positive bacteria in house dust in the low-allergy risk Russian Karelia. Environ Microbiol

2008;10:3317-3325.

2. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrländer C, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011;364:701-709.

3. Mackay D, Haw S, Ayres JG, Fis-chbacher C, Pell JP. Smoke-free legislation and hospitalizations for childhood asthma. N Engl J Med 2010;363:1139-1145.

4. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006;355:2226-2235.

Figure 1 Prevalence of asthma and atopy in Karelian children. (Data from von Hertzen L, Mäkelä MJ, Petäys T, et al. Growing disparities in atopy between the Finns and the Russians: a comparison of 2 generations. J Allergy Clin Immunol. 2006;117:151-

157.)

Figure 2 Protective environment in a traditional farm.


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Pro

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1.0

0.8

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No. of Detectable Bands

B Fungi (GABRIELA)A Bacteria (PARSIFAL)

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No. of Detectable Taxa

Living on a farm Living on a farm

AsthmaAsthma

Figure 3 The diversity of microbial exposure is inversely related to asthma. (From N Engl J Med, Ege MJ, Mayer M, Normand, et al. Exposure to environmental microorganisms and childhood asthma, 364, 701-709 Copyright © 2011 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.)

Figure 4 Decreased hospital admission for asthma after tobacco smoke ban in Scotland. (From N Engl J Med, Mackay D, Haw S, Ayres JG, et al. Smoke-free legislation and hospitalizations for childhood asthma, 363, 1139-1145 Copyright © 2010

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

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Epidemiological, clinical, and mech-anistic research demonstrates that viral, bacterial, and fungal infec-tions, and commensal bacteria (mi-crobiome), are strongly associated with asthma development and dis-ease activity.

ASTHMA DEVELOPMENTViral bronchiolitis in young children is associated with an increased risk of recurrent wheeze and childhood asthma. Respiratory syncytial virus (RSV) accounts for about 70% of bronchiolitis cases. In a Swedish longitudinal case/control study, severe RSV-bronchiolitis in infan-cy was the strongest risk factor for asthma development, independent of parental asthma or allergy, and remained associated with marked-ly elevated rates of asthma, allergic rhinitis and aero-allergen sensi-tisation at the age of 18 years. An even higher asthma risk follows rhinovirus (RV)-induced wheezing illness in infancy. In a birth cohort of children from atopic/asthmat-ic parents, allergic sensitisation preceded RV-wheezing illness and may have been required for its development. Whether early life bronchiolitis causes, contributes to and/or is a marker of asthma development still remains to be determined. The observation that

premature infants who received passive immunisation against RSV (palivizumab), had less than half the risk of recurrent wheeze at 2-5 years of age, suggests that viral bronchiolitis does indeed contrib-ute to asthma development. In ad-dition to viruses, neonatal carriage of pathogenic bacteria, including Streptococcus pneumoniae, Haemo-philus influenzae and Moxarella ca-tarrhalis, has also been implicated in the development of childhood asthma.

ASTHMA SEVERITY AND ExACERBATIONSIn established asthma airway car-riage of Haemophilus influenzae and Streptococcus pneumoniae is more frequent than in health and commensal bacteria of the Phylum bacteroidetes are lacking. The abun-dance of other airway commensals (Comamonadaceae, Sphingomona-daceae, Oxalobacteraceae) corre-lates with the degree of bronchial hyper-responsiveness, a marker of disease severity. Importantly, asth-ma increases the risk of invasive

Ke y m e ssag e s• Viral bronchiolitis in early childhood is associated with an

increased risk of asthma development.• Respiratory viruses, notably rhinoviruses, are the most important

triggers of asthma exacerbations in both children and adults.• Pathogenic bacteria, including atypical bacteria, and the

composition of airway commensals (microbiome) can influence disease activity in asthma.

• Asthma increases the severity of respiratory viral infections and the risk of invasive pneumococcal infection.

• Fungal infection of the airways can provide high loads of allergens aggravating allergic asthma.

• Some infections, including helminth parasites, may protect against asthma.

• Understanding the mechanisms by which microbial components promote or inhibit asthma might provide the basis for prevention and curative treatment of asthma

INFECTIONS AND ASTHMA14Jürgen Schwarze

The University of Edinburgh UK

Infections and asthma

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pneumococcal infection.

Fungal allergens often drive aller-gic asthma and both fungal col-onisation and infection, e.g. with Aspergillus, can aggravate allergic asthma through increased allergen exposure and infection induced in-flammation.

Most acute asthma exacerbations (AAEs) are triggered by respiratory viral infections, with RVs being de-tected in up to 80% of AAEs in chil-dren and 65% in adults (Figure 1). Asthmatics develop more severe respiratory symptoms in RV-in-fection than non-asthmatic con-trols, possibly due to lower type-1 interferon responses of infected epithelial and resulting reduced viral control. Infections with the recently discovered species RV-C may result in particularly severe AAEs. Other viruses associated with AAEs include enteroviruses, RSV, influenza virus, coronavirus,

metapneumovirus and parainflu-enza viruses. Importantly, in aller-gic asthma AAEs are most severe if a viral infection coincides with exposure to an asthma-driving al-lergen (Figure 2).

The atypical bacteria Chlamydia pneumoniae and Mycoplasma pneu-moniae are also frequently detect-ed in asthma and may increase the risk and severity of AAEs. Treat-ment with macrolides can reduce the severity of AAEs, which may be due to their antimicrobial ef-fects on atypical bacteria, but also to independent anti-inflammatory properties.

The mechanisms by which infec-tions contribute to asthma devel-opment and disease activity are thought to include: damage to the mucosal airway barrier with increased infection risk and aller-gen up-take; heightened innate pro-inflammatory and pro-allergic

responses from infected epithelial cells, fibroblasts and immune cells; enhanced adaptive immune re-sponses to allergens; increased air-way remodelling; delayed resolu-tion of inflammation; hyperactivity and proliferation of airway nerves.

INFECTIONS PROTECTING FROM ASTHMAExperimental models suggest that some infections, including with mycobacteria, E. coli and helminths can inhibit asthma. Endemic hel-minth infections have been asso-ciated with a low prevalence of atopy. In animal models, helminth infections can suppress the devel-opment of allergic airways disease.

Enhanced understanding of the microbial components and mech-anisms that promote or inhibit asthma is necessary to provide the basis for prevention and curative treatment of asthma, both of which are currently lacking.

Figure 1 Viruses and bacteria associated with asthma exacerbations. The prevalence of viruses and bacteria in young children (<2 years old), older children (6–17 years old) and adults, presented as median percentages from several studies.

Enterovirus estimations in adults and bocavirus estimations in 6–17 year olds and in adults may be under-represented since data is not available in published studies. (Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Microbiol, Edwards

MR, Bartlett NW, Hussell T, et al, The microbiology of asthma, 10, 459-471, copyright 2012.)

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Figure 2 Respiratory viruses interact with allergens to promote asthma. Following sensitization, allergen presentation by airway dendritic cells (DCs) facilitates the promotion of T helper 2 (T

H2) cells. Viruses infect epithelial cells, stimulating

the release of TH

2 cell-promoting chemokines CC-chemokine ligand 17 (CCL17) and CCL22, and cytokines thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL-33. The T

H2 type chemokines attract T

H2 cells into the airway, and

these in turn secrete IL-4, IL-5 and IL-13. IL-5 promotes eosinophilia, and the resultant eosinophils release the inflammatory mediators major basic protein (MBP), eosinophil cationic protein (ECP) and transforming growth factor-β (TGF-β), inducing

inflammation in the airway smooth muscle (ASM). IL-4 and IL-13 cause antibody class switching to immunoglobulin E in B cells, so that B cells secrete allergen-specific IgE. This antibody then binds mast cells, and crosslinking of the

allergen on mast cell-bound IgE causes mast cell degranulation and release of preformed mediators, including histamine, prostaglandin (PGD

2) and leukotrienes (LTC

4, LTD

4 and LTE

4). These mediators cause bronchoconstriction and further

airway inflammation. Mast cells also produce the TH

2 cytokines IL-4 and IL-13, as well as other cytokines, including TGFβ and tumour necrosis factor (TNF), promoting further T

H2 type immune responses and inflammation. (Reprinted by permission

from Macmillan Publishers Ltd: Nat Rev Microbiol, Edwards MR, Bartlett NW, Hussell T, et al, The microbiology of asthma, 10, 459-471, copyright 2012.)

KEY REFERENCES1. Edwards MR, Bartlett NW, Hus-

sell T, Openshaw P, Johnston SL. The microbiology of asthma. Nat Rev Microbiol 2012;10:459-471.

2. Tregoning JS, Schwarze J. Res-piratory viral infections in infants: causes, clinical symptoms, virolo-gy, and immunology. Clin Microbiol Rev 2010;23:74-98.

3. Papadopoulos NG, Christodoulou I, Rohde G, Agache I, Almqvist C, Bruno A, et al. Viruses and bac-teria in acute asthma exacerba-tions--a GA² LEN-DARE systemat-ic review. Allergy 2011;66:458-68.

4. Gavala ML, Bertics PJ, Gern JE. Rhinoviruses, allergic inflamma-tion, and asthma. Immunol Rev 2011;242:69-90.

5. Johnston SL, Blasi F, Black PN,

Martin RJ, Farrell DJ, Nieman RB,

et al. The effect of telithromycin

in acute exacerbations of asthma.

N Engl J Med 2006;354:1589-600.

6. Flohr C, Quinnell RJ, Britton J. Do

helminth parasites protect against

atopy and allergic disease? Clin Exp Allergy 2009;39:20-32.


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Despite considerable research over the last few decades, we still have an incomplete understanding of why and how asthma develops. As the previous chapters have de-scribed, a number of epidemiolog-ical factors and specific genotypic variants have been associated with asthma. None though massively increase the chances of an individ-ual developing asthma in a manner that, for example, exposure to cig-arette smoke dramatically increas-es your chance of developing lung cancer. So, we are still attempting to understand the full story. This is therefore a good time to take a step back, consider why this may be the case and think about how we can better understand the de-velopment of asthma in the future.

The factors that are seen to asso-ciate with asthma in studies are heavily influenced by the nature of the patients, who participate in the study. Usually asthma is defined as a doctor’s diagnosis of asthma with or without the need for evidence of reversibility with a bronchodi-lator. Doctors diagnose asthma on the basis of a syndrome of clin-ical features, for example episodic wheeze or chest tightness in asso-ciation with specific triggers. Many different pathological mechanisms

can result in airway obstruction, which can give rise to the features of asthma. A clinician might recog-nise viral-associated asthma, ex-ercise-induced asthma or allergic asthma while a histopathologist might recognise eosinophilic or neutrophilic asthma. The patient will be diagnosed as having asthma, despite different pathophysiology and precise clinical presentation. Different factors are very likely to be important in promoting the development of different type of asthma (Figure 1). For example, in the isle of Wight birth cohort ma-ternal asthma and chest infections in early childhood were risk factors for non-atopic wheeze while co-ex-

isting allergic diseases and male gender were risk factors for atop-ic wheeze. Additionally, different factors may interact to modulate each other’s effects. For example, in a study on farm living, specific alleles in the pattern-recognition receptor CD14 promoter region were associated with less risk of asthma, but only if farm milk was consumed.

So, we have a situation where we have subpopulations of individuals who have different genetic suscep-tibilities to different pathophysio-logical mechanisms that could give rise to asthma. Whether or not they develop asthma will depend

Ke y m e ssag e s• Different factors are very likely to be important in promoting the

development of different types of asthma• Risk and protective factors may interact to modulate each others

effects• Large studies with well characterised populations need to be

undertaken using a gene-environmental interaction approach• A number of studies suggest that suboptimal fetal growth is

associated with later asthma• Deficient innate immune response might preceed the onset of

asthma• The relationship between low intake of specific micronutrients or

a specific diet and the later onset of asthma remains to be proven

EMERGING RISK AND PROTECTIVE FACTORS FOR

ASTHMA15

Graham Roberts University of Southampton

UK

Emerging risk and protective factors for asthma

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on what they are exposed to in their environment. That means an individual with a specific suscep-tibility may develop asthma in one environment, but not in another (Figure 1). A simple analysis within a genetically homogeneous popu-lation or with minimal variability in exposure to different environ-mental exposures will fail to uncov-er this complexity. Larger studies with well characterised popula-tions need to be undertaken using a gene-environment interaction approach. We also need to better capture the heterogeneity in asth-

ma phenotypes. Researchers are beginning to do this using unbiased approaches and systems medicine modelling for asthma and allergic disease.

What novel risk and protective factors (Figure 2) should these studies focus on? There are now a number of studies that suggest that suboptimal fetal growth is as-sociated with later asthma. Larger birth cohort studies with fetal ul-trasound assessments and infant lung function measures are need-ed to understand how suboptimal fetal growth impacts on childhood

asthma, particularly in relationship with other factors such as atopy and innate immune response. The role of viruses in the pathogenesis of asthma has been actively dis-cussed for many years. The miss-ing factor in these discussions has been the innate immune response, for example, deficient anti-viral interferon response. We need to understand whether or not the deficient innate immune response pre-dates the onset of asthma. Fi-nally, many studies have looked, with varying successful for rela-tionships between low intake of

Figure 1 Impact of different environmental factors on individuals with differing genetic susceptibility to give rise to different asthma phenotypes. Exposure to specific environmental factors (green boxes) will give rise to specific asthma

phenotypes (red boxes) in individuals with specific genotypic susceptibility profiles (blue boxes). One environmental factor may have very different impacts on individuals with different genotypic susceptibilities.

Susceptibility genotypes 1



Susceptibility genotypes X

Asthma phenotype 1

Asthma phenotype 2

Asthma phenotype 3

Asthma phenotype X

Asthma diagnosis:• Episodic wheeze,

shortness of breath, chest tightness

• Specific triggers• Reversible with

bronchodilators

Environmental factor 1




Environmental factor X

+

+

+

+

+

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specific micronutrients and the later onset of asthma. But evolu-tionally we have developed eating a diet that consists of a range of micronutrients and so it might be expected that dietary patterns are more likely to be related to the de-velopment of asthma than levels of individual micronutrients.

KEY REFERENCES1. British Thoracic Society, Scottish

Intercollegiate Guidelines Net-work. British Guideline on the Management of Asthma. Thorax 2008;63:iv1-121.

2. Kurukulaaratchy RF, Fenn M, Mat-thews S, Arshad SH. Character-isation of atopic and non-atopic wheeze in 10 year old children. Thorax 2004;59;563-568.

3. Bieli C, EderW, Frei R, Braun-Fahrländer C, Klimecki W, Waser M, et al. A polymorphism in CD14 modifies the effect of farm milk consumption on allergic diseases and CD14 gene expression. J Aller-

gy Clin Immunol 2007;120:1308-1315.

4. Auffray C, Adcock IM, Chung KF, Djukanovic R, Pison C, Sterk PJ. An integrative systems bi-ology approach to understand-ing pulmonary diseases. Chest 2010;137:1410-1406.

5. Antó JM, Pinart M, Akdis M, Auf-fray C, Bachert C, et al. Under-standing the complexity of IgE-re-lated phenotypes from childhood to young adulthood: A Mecha-nisms of the Development of Al-lergy (MeDALL) Seminar. J Allergy Clin Immunol 2012;129:943-954.

6. Pike KC, Crozier SR, Lucas JS, In-skip HM, Robinson S; Southamp-ton Women’s Survey Study Group, et al. Patterns of and infant growth are related to atopy and wheezing disorders at age 3 years. Thorax 2010;65:1099-1106.

7. Pike KC, Rose-Zerilli MJ, Osvald EC, Inskip HM, Godfrey KM, Cro-zier SR, et al. The relationship between infant lung function and

the risk of wheeze in the pre-school years. Pediatr Pulmonol 2011;46:75–82.

8. Turner S, Zhang G, Young S, Cox M, Goldblatt J, Landau L, et al. Associations between postnatal weight gain, change in postna-tal pulmonary function, formula feeding and early asthma. Thorax 2008;63:234-239.

9. Baraldo S, Contoli M, Bazzan E, Turato G, Padovani A, Marku B, et al. Deficient antiviral immune responses in childhood: Distinct roles of atopy and asthma. J Aller-gy Clin Immunol 2012;130:1307-1314.

10. Allan K, Devereux G. Diet and Asthma: Nutrition Implications from Prevention to Treatment. J Am Diet Assoc 2011;111:258-268.

11. Gale CR, Martyn CN, Marriott LD, Limond J, Crozier S, Inskip HM, et al. Dietary patterns in infancy and cognitive and neuropsychological function in childhood. J Child Psy-chol Psychiatry 2009;50:816-823.

Figure 2 Novel risk and protective factors for asthma: fetal growth, anti-viral interferon response and diet.

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Over the last decade, there has been significant advances in our understanding of the mechanisms governing susceptibility to asthma development during childhood. Most notably, it has become clear that there are two major sets of en-vironmental influences responsible for the airways inflammation that drives asthma induction. The first of these is early postnatal sensiti-zation to perennial aeroallergens, and the second is lower respirato-ry viral infections. A wide body of epidemiological evidence suggests that both these environmental in-sults can act independently in driv-ing asthma development, but risk is maximised if they occur concomi-tantly, inferring some form of syn-ergistic interaction between the underlying inflammatory pathways they trigger. Thus, as illustrated in Figure 1, environmental exposures initiate inflammation-driven cycles responsible for transient airway symptoms, but the resulting re-pair/regeneration responses lead to persistent pathological changes associated with tissue remodel-ling, resulting in long term effects on respiratory function. These ef-fects are most profound in relation to inflammatory cycles occurring during early childhood when lung growth and differentiation are pro-

gressing most rapidly.

It is clear that similar interactions underlie moderate-severe asthma exacerbations in older children, as the phenotypic features of these events reflect the same pattern of comorbidities in affected subjects (atopy plus respiratory infections). In this regard there has also been significant recent progress in elu-cidation of the nature the inter-actions between inflammatory pathways triggered by concom-itant exposure to aeroallergens and viruses, employing virus-as-

sociated asthma exacerbations as windows into the underlying pro-cesses. Notably, initial interferon (IFN)-associated signals generated in the infected airway mucosa in the early stages of exacerbation events lead to upregulation of FcεR1-expression on resident den-dritic cells (DC), facilitating mark-edly enhanced presentation of aeroallergen signals to transiting allergen-specific Th2-memory cells and an ensuing local Th2 cytokine ”storm” that antagonizes Th1-as-sociated viral clearance (Figure 2). Subsequent translocation of

Ke y m e ssag e s• Two major sets of environmental influences, acting independently

or synergising, are responsible for asthma induction: early postnatal sensitization to perennial aeroallergens and lower respiratory viral infections

• These effects are most profound in early childhood, but similar interactions underlie asthma exacerbations in older children

• Initial signals generated in the viral infected airway mucosa trigger a local Th2 cytokine “storm” that antagonizes Th1-associated viral clearance and boost a “tissue-to-tissue spread” of allergic inflammation

• Nasopharyngeal colonization during infancy with bacterial pathogens or low levels of bacteria in the conducting airways have been associated with asthma risk

• However, Th2 immunity to mucosal dwelling bacteria and prenatal bacterial exposure were associated with reduced risk for asthma

PERINATAL AND EARLY LIFE INFLUENCES ON ASTHMA

DEVELOPMENT16

Patrick G. Holt The University of Western Australia

Perth, Australia

Perinatal and early life influences on asthma development

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Figure 1 The inflammatory cycle in asthma pathogenesis. Asthma development is driven by repeated cycles of

inflammation triggered by airborne irritant stimuli (top). Symptoms are initially intermittent and are associated with

acute inflammation and edema and intermittent airway narrowing. Over time, the resolution of inflammation between clinically apparent episodes of asthma becomes less complete.

Persistent inflammation leads to repeated cycles of tissue repair and regeneration, which may themselves be aberrant,

and can lead to pathological changes that persist for long periods. As these changes accumulate, they lead to progressive

deterioration in respiratory function (bottom). Once these changes exceed a critical threshold, they may not be

reversible and may result in persistent asthma, with persistent symptoms that are not easily controlled by currently approved medications. (Reprinted by permission from Macmillan Publishers

Ltd: Nat Med, Holt PG, Sly PD, The microbiology of asthma, 18, 726-735, copyright 2012.)

both Th2 and IFN signals to bone marrow results in generation of lung-homing “alternatively activat-ed” macrophages associated with tissue repair/remodeling, and also stimulates upregulation of FcεR1 on lung-homing DC precursors that further amplify subsequent expression of local Th2 immunity.

It is additionally clear that translo-cation of FcεR1-stimulatory signals from sites of allergic inflammation to bone marrow also occurs in the absence of virus infection. While these signals are less intense than those in Figure 2, they neverthe-less also result in significant upreg-ulation of FcεR1 in the circulating myeloid cell compartment. This population supplies precursors to replenish DC in all peripheral tis-sues, and this provides a potential mechanism for “tissue-to-tissue spread” of allergic inflammation (Figure 3).

While the major emphasis in re-lation to microbial risk factors in asthma development is currently on viruses, emerging evidence also points to an important additional role for bacteria. Notably, naso-pharyngeal colonization during in-fancy with bacterial pathogens has been associated with risk for early onset asthma. Moreover, the pres-ence of low levels of bacteria in the conducting airways has also been associated with asthma risk in old-er subjects. It is feasible that bacte-ria that broach the airway epitheli-um during virus-associated asthma exacerbations when local mucosal “barrier” functions are compro-mised, may amplify local tissue damaging inflammatory responses via interactions with local mac-rophages (Figure 2). In this context, it is noteworthy that recent find-ings indicate that underlying Th2 immunity to mucosal dwelling bac-teria in children is associated with

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Figure 2 Virus associated atopic asthma exacerbations: harnessing aeroallergen specific IgE via FCεR1 on dendritic cells. Viral initiated production of Type 1 IFN in the airway mucosa of atopic asthmatics triggers a cascade including a

bone marrow mediated amplification loop, through which Th2 immunity is recruited into the host defense response to the pathogen. Potential consequences include attenuation of sterilizing immunity and hence persistence of virus, and

unmasking of susceptibility to the pro-inflammatory effects of airway mucosal dwelling bacteria. (Reproduced with permission from the American College of Chest Physicians from Holt PG, Sly PD. Interaction between adaptive and innate immune pathways in

the pathogenesis of atopic asthma: operation of a lung/bone marrow axis. Chest 2011;139:1165-1171.)

reduced risk for asthma, likely via IL-4/IL-13-mediated attenuation of bacterial-induced macrophage activation in the airways following bacterial invasion.

It is pertinent also to note contra-dictory data associated with pre-natal bacterial exposure. In par-ticular, epidemiological evidence suggesting reduction in asthma risk in children of mothers who ex-perience high exposure to airborne bacteria during pregnancy has re-cently been complimented by ani-mal model studies confirming the

phenomenon, and demonstrating a key role for the maternal TLR sys-tem in mediating these effects. The target for this mechanism appears to be the fetomaternal interface, possibly involving dampening of local inflammatory mechanisms which can interfere with placental function.

KEY REFERENCES1. Holt PG, Sly PD. Viral Infections

and atopy in asthma pathogene-sis: new rationales for asthma pre-vention and treatment. Nat Med 2012;18:726-735.

2. Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies. J Allergy Clin Immunol 2005;116:16-24.

3. Olenec JP, Kim WK, Lee WM, Vang F, Pappas TE, Salazar LE, et al. Weekly monitoring of chil-dren with asthma for infections and illness during common cold seasons. J Allergy Clin Immunol 2010;125:1001-1006.e1.

4. Sly PD, Boner AL, Björksten B, Bush A, Custovic A, Eigenmann


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Figure 3 The “atopic march” – systemic spread of allergic reactivity between tissues. The bone marrow amplification loop depicted in Figure 2 also operates in allergic inflammatory responses in the absence of viral comorbidity, albeit at lower

levels of intensity. Under such circumstances, chronic allergic diseases such as allergic rhinitis triggered by aeroallergens, initially in the absence of concomitant asthma exacerbations, has potential to increase the likelihood of the eventual

development of asthmatic-like responses via enhancing the Th2-stimulatory functions of airway mucosal dwelling APC. (Reprinted by permission from Macmillan Publishers Ltd: Nat Med, Holt PG, Sly PD, The microbiology of asthma, 18, 726-735,

copyright 2012.)

PA, et al. Early identification of atopy in the prediction of persis-tent asthma in children. Lancet 2008;372:1100-1106.

5. Subrata LS, Bizzintino J, Mamess-ier E, Bosco A, McKenna KL, Wik-ström ME, et al. Interactions be-tween innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma ex-acerbations in Children. J Immunol 2009;183:2793-2800.

6. Bisgaard H, Hermansen MN, Bu-chvald F, Loland L, Halkjaer LB, Bønnelykke K, et al. Childhood asthma after bacterial coloniza-tion of the airway in neonates. N Engl J Med 2007;357:1487-1495.

7. Hilty M, Burke C, Pedro H, Carde-nas P, Bush A, Bossley C, et al. Dis-ordered microbial communities in asthmatic airways. PLoS One 2010;5:e8578.

8. Conrad ML, Ferstl R, Teich R,

Brand S, Blümer N, Yildirim AO, et al. Maternal TLR signaling is required for prenatal asthma pro-tection by the nonpathogenic mi-crobe Acinetobacter lwoffii F78. J Exp Med 2009;206:2869-2877.

9. Hollams EM, Hales BJ, Bachert C, Huvenne W, Parsons F, de Klerk NH, et al. Th2-associated immu-nity to bacteria in teenagers and susceptibility to asthma. Eur Respir J;36:509-516.

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Since the beginning of the 20th century it has been recognised that asthma is a condition in which psychological factors have a ma-jor role. Clinicians recognise that emotional stress can precipitate or exacerbate asthma and that a patient’s psychological status may affect their asthma control, by im-pacting on symptom presentation and treatment adherence (Figure 1). Thus, the relationship between asthma and psychological factors can be described as bi-directional.

PSYCHOLOGICAL STATUS AND PSYCHIATRIC CO-MORBIDITY IN PATIENTS WITH ASTHMAAsthmatics tend to report high lev-els of negative emotions, and asth-ma exacerbations have been linked temporally to periods of height-ened emotionality. The prevalence of depressive disorders is proba-bly higher in people with asthma relative to the general population: a wide range of prevalence esti-mates have been reported, with some exceeding 40%. Interestingly, a relationship between depression and asthma is evident in families as well as in individuals; familial stud-ies suggest that the prevalence of each disorder is higher in the fami-ly members of index cases with the other.

Patients with bipolar affective dis-orders also appear to have a higher risk than the general population of developing IgE-mediated aller-gic conditions, including asthma. Similarly, there is an increased prevalence of anxiety disorders in asthma, affecting as many as one third of asthmatic children and ad-olescents, and 24% of adults with asthma.

Unfortunately, the literature on the prevalence of psychological and psychiatric disorders in asth-matics is complicated by unclear disease definitions, differences in

nomenclature, small samples and a focus on outpatient or inpatient populations rather than the com-munity.

The World Mental Health Survey goes some way to address these methodological problems and provides standardised data for 17 countries worldwide (Table 1). The pooled estimates of age- and sex-adjusted odds of mental dis-orders among patients with asth-ma comparative to those without asthma were 1.6 (95% CI=1.4, 1.8) for depressive disorders and 1.5 (95% CI=1.4, 1.7) for anxiety disor-

Ke y m e ssag e s• Asthma is associated with significant psychological burden and

psychiatric co-morbidity• Psychological distress may play a role in the perception of asthma

symptoms and asthma treatment (e.g. adherence, health seeking behaviours), which in turn impacts on prognosis, morbidity and mortality

• There is global consistency in the relationship between asthma and mental disorders

• Adopting a bio-psychosocial approach when consulting with a patient with asthma ensures that the wider consequences of asthma and not just their physical symptoms are addressed

• Psychological interventions are used to augment pharmacological management of asthma but there is currently limited evidence of their effectiveness

PSYCHOLOGICAL FACTORS AND ASTHMA17Helen Smith

Brighton and Sussex Medical School UK

Psychological factors and asthma

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Figure 1 How might low mood or anxiety impact on asthma?

ders. This study also demonstrat-ed a relationship between asthma and alcohol use disorders (OR 1.7 (95% CI=1.4, 2.1). Although the prevalence of mental disorders and asthma varies greatly between countries, the association of the two showed much less cross-sec-tional variability. This consistency is fascinating given that the coun-tries included differ significantly in their culture, organisation of health services and stage of soci-oeconomic development. It indi-cates that wherever setting clini-cians work, they need to be aware of the significant overlap of asthma with psychological and psychiatric disorders.

WHAT LINKS PSYCHOLOGICAL DISTRESS AND ASTHMA?Early psychosomatic models sup-ported a role for psychological distress in contributing to variable asthma morbidity among those

with existing disease, but growing knowledge of patho-physiological pathways suggests a role for psy-chological factors also in the gen-esis of asthma. Asthma and major depressive disorders have similar patterns of dysregulation of key biological systems including the neuro-endocrine stress response, cytokines, and neuropeptides. Twin-pair studies provide addi-tional evidence of a genetic link between atopic and depressive symptoms. Further work is needed to unravel these relationships.

PSYCHOLOGICAL INTERVENTIONS AND TREATMENTS FOR ASTHMA Recognising the relationship be-tween asthma and psychologi-cal factors psychological inter-ventions are sometimes used to complement the pharmacological management of asthma. Many dif-ferent therapies have been tried,

including behavioural therapies, cognitive therapies, cognitive-be-havioural therapy, relaxation tech-niques, psycho-dynamic psycho-therapies and counselling (both for the individual and for the family). However, unlike pharmacological therapies for asthma, we still have very limited evidence of the effec-tiveness of these psychological in-terventions in children or adults.

This paucity of evidence arises be-cause studies of psychological in-terventions for asthma have often not been randomised, and those studies that have used randomised controlled methodology have lacked power to confirm the utility of the intervention. Furthermore, combining studies in systematic reviews and meta-analyses is limit-ed by the diversity of interventions used, and the variety of different outcomes measured. In a Cochrane review of psychological interven-

Changes in Health Behaviour Constructs

• Decreased self-efficacy to manage asthma

• Decreased internal locus of control

• Increased anxiety or fear in response to asthma symptoms

Psychological Disorder

anxiety or low mood

Poorer Asthma Management

• Decreased adherence to medication, peak flow monitoring, smoking cessation

• Delay in seeking treatment

• Failure to avoid en-vironmental irritants/allergens

• Distorted symptom presentation

Poorer Asthma Outcomes

• Increased asthma symptoms

• Decreased lung function

• Asthma exacerbations• Increased morbidity

and costs

Adverse Social Impacts

• Reduced self-confidence• Decreased quality of life• Time lost from work or education• Adverse impact on relationships (family, friends)• Social stigma

“Negative feedback loop”

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TABLE 1

Odds Ratio (age - sex adjusted) for mental disorders amongst adults with asthma versus without asthma

CountryWeighted

asthma prevalance %

Major Depression

OR

Dysthymia OR

General Anxiety

OR

Panic Disorder

OR

Social Phobia OR

Post trau-matic stress disorder OR

Alcohol Use Disorder

OR

Americas

Colombia 3.0 3.8 7.5 0.6 2 1.1 - 8.9

Mexico 2.2 1.2 0.7 - 0.7 2.9 3.6 1.6

United States 11.6 1.4 1.7 1.7 1.3 1.0 1.3 1.8

Asia and South Pacific

Japan 5.4 1.2 0.9 1.7 0.8 3.8 4.3 1.6

Beijing, PRC 2.3 2.5 2.8 2.9 - 5.0 - 0.9

Shanghai, PRC 5.1 1.4 - - - - - 0.8

New Zealand 17.2 1.5 1.5 1.7 1.5 1.1 1.8 1.5

Europe

Belgium 5.8 1.2 0.2 4 - 0.9 0.5 0.9

France 7.5 1.5 2.6 2.8 0.8 2.1 3.3 0.6

Germany 4.5 2.1 5.4 - 4.1 1.0 - 1.8

Italy 4.6 2.2 1.6 - 0.4 3.2 2.8 -

The Netherlands 8.5 1.4 1.6 0.6 3.0 1.4 5.5 2

Spain 5.7 2.7 2.5 2.8 1.6 8.1 3.8 2.9

Ukraine 1.8 2.7 3.6 1.2 6.0 0.8 4.1 5.4

Middle East and Africa

Lebanon 1.2 - - - - - - -

Nigeria 0.6 - - - - - - -

Israel 7.2 1.4 1.1 1.2 1.7 - 0.6 1.7

South Africa 5.8 2.1 - 2.7 2.6 3.1 0.8 1.4

Odds Ratio (OR) is not listed if fewer than 25 respondents have asthma or if the cross classification of mental disorder and asthma is null. PRC - People’s Republic of China. (Data from Scott KM, Von Korff M, Ormel J, et al. Mental disorders among adults with asthma:

results from the World Mental Health Survey. Gen Hosp Psychiatry 2007;29:123-133.)

tions for adults, meta-analysis identified the positive effect of cog-nitive behaviour therapy on quality of life, biofeedback on peak expir-atory flow rate (PEFR), and relaxa-tion therapy on medication use. In the equivalent review for children, relaxation therapy improved PEFR. Both reviews concluded that it was not possible to endorse psycholog-ical interventions on the basis of current literature.

Clinicians’ observations of posi-tive benefit for individuals from psychological interventions may challenge the formal review of the literature. In part this discrepancy

may arise because in clinical prac-tice psychological treatments are often reserved for distressed pa-tients with severe or poorly con-trolled asthma whereas trials often recruit patients with milder and more controlled asthma, and have often failed to screen participants for psychological distress at inclu-sion, resulting in study populations that are less able to benefit (ceiling effect) from psychological inter-vention. Well designed trials are urgently needed.

KEY REFERENCES1. Scott KM, von Korff M, Ormel J,

Zhang MY, Bruffaerts R, Alons J, et

al. Mental disorders among adults with asthma: results from the World Mental Health Survey. Gen Hosp Psychiatry 2007;29:123-133.

2. Van Lieshout RJ, MacQueen G. Psychological factors in Asth-ma. Allergy Asthma Clin Immunol 2008;4:12-28.

3. Yorke J, Fleming SL, Shuldham C. Psychological interventions for adults with asthma. Cochrane Database Syst Rev 2006; Art. No.: CD002982.

4. Yorke J, Fleming SL, Shuldham C. Psychological interventions for children with asthma. Cochrane Database Syst Rev 2005; Art. No.: CD003272.


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A large variability in asthma rates across the world and a sharp rise in its prevalence in the last dec-ades strongly suggest a crucial role of environmental factors in the causation of asthma. However, knowledge about the underlying cause(s) of asthma epidemics re-mains elusive. The answer is likely to lie in our environment and life-style, which have undergone pro-found changes in a relatively short period of time (including changes in housing design, exposure to pol-lutants, microbial exposure, family size and childcare arrangements, diet, sedentary life style and exer-cise).

A striking difference for incidence of asthma between urban and ru-ral areas within one country has been consistently reported from many different parts of the world. Individuals who move from rural areas into cities are retaining this protection. Higher risk of asthma has been consistently associated with various markers of affluence (including decreasing family size and high socio-economic status), all of which may reflect eradication of infections (e.g. through vaccina-tion programmes), increased clean-liness and modern diet. However, it is of note that in some areas of

the world (e.g. South America and inner-city USA) poverty has been related to asthma.

The “hygiene hypothesis” suggests that reduced exposure to infec-tions in early life may delay matu-ration of the immune system and favour allergic responses and asth-ma. For example, protective effect of contact with other children has been consistently reported using early life day-care entry as proxy of exposure. Similar protection has been observed in relation to contact with animals (in particular dogs and farm animals). Probably the most consistent protective ef-

fect against asthma has been re-ported for farming environments. Data from Europe indicate that the protective effect of farming on asthma is confined to traditional types of farms (e.g. with cows and cultivation).

All of these factors (crowding, day-care facilities, pet ownership and farming) may be markers of an in-creased exposure to various micro-bial compounds (including, but not confined to endotoxin). Infections with pathogens (such as Salmonel-la, Toxoplasma gondii, mycobacteria etc.) may also be protective, al-though the reported associations

Ke y m e ssag e s• Environmental factors play a crucial role in asthma epidemics• Higher risk of asthma is associated with markers of affluence• Reduced exposure to infections in early life may favour allergic

responses and asthma• Asthma development is influenced by numerous environmental

exposures• The effect of specific environmental exposures is different

amongst individuals with different genetic predispositions• Only individuals with particular predisposition will benefit from

a specific intervention aimed at asthma prevention; the same intervention amongst individuals with different susceptibility may cause harm

• “One size fits all” approach to asthma prevention and treatment has to be replaced by a personalised, stratified approach

THE COMPLEx NETWORK OF ASTHMA RISK AND PROTECTIVE FACTORS

18Adnan Custovic

University of Manchester UK

The complex network of asthma risk and protective factors

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may reflect unhygienic living con-ditions.

Some types of outdoor air pollution (in particular traffic exposure) may have adverse effects on asthma. In-door pollutants, especially environ-mental tobacco smoke exposure, also contribute to asthma morbid-ity. Allergen exposure in homes has attracted considerable interest as a potential contributing factor. High allergen exposure amongst allergic asthmatic patients is asso-ciated with more severe disease; however, the relationship between allergen exposure and asthma de-velopment is more complex. For example, cockroach infestation is a strong risk for cockroach sensiti-sation and asthma morbidity (espe-cially in the US inner-city homes), but it is unlikely that indoor aller-gen exposure has direct role of in asthma development.

A complex relationship between genetic predisposition and envi-ronmental exposures in the devel-opment of asthma has received increasing attention over the last decade. Development of asthma may be influenced by a number of different environmental expo-sures, but genetic predisposition of the individual plays a critically important role, in that the effect of specific environmental exposures is different amongst individuals

with different genetic predisposi-tions. Recent examples of gene-en-vironment interactions include the observation of the opposite effect of day-care attendance in the first year of life on asthma development in children with different vari-ants in the TLR2 gene. Day-care appeared protective in the whole population, concealing the fact that in a subgroup of genetically susceptible individuals, attending day-care increased the risk of asth-ma.

Additional level of complexity is added by the increasing evidence that the effect of environmental exposures on asthma strongly de-pends on the timing of exposure. Throughout early life, children un-dergo a constant process of devel-opment and maturation. It seems likely that there are “windows of opportunity” during certain stages of development when individuals may be particularly vulnerable to extrinsic influences. Furthermore, prenatal factors (e.g. maternal ex-posures during pregnancy) may play an important role, either through direct effects acting in ute-ro, or via epigenetic modifications.

Asthma arises as a consequence of environmental factors modulating the risk in genetically susceptible individuals through gene-envi-ronment interactions. As a conse-

quence, only individuals with par-ticular susceptibility will benefit from a specific intervention aimed at asthma prevention; the same intervention amongst individuals with different susceptibility may cause harm.

KEY REFERENCES1. Illi S, Depner M, Genuneit J, Horak

E, Loss G, Strunz-Lehner C, et al. Protection from childhood asthma and allergy in Alpine farm environ-ments-the GABRIEL Advanced Studies. J Allergy Clin Immunol 2012;129:1470-1477 e6.

2. Custovic A, Simpson A. The role of inhalant allergens in allergic air-ways disease. J Investig Allergol Clin Immunol 2012;22:393-401.

3. Custovic A, Marinho S, Simpson A. Gene-environment interactions in the development of asthma and atopy. Expert Rev Respir Med 2012;6:301-308.

4. Custovic A, Rothers J, Stern D, Simpson A, Woodcock A, Wright AL, et al. Effect of day care at-tendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. J Allergy Clin Immunol 2011;127:390-397 e1-9.

5. Martino D, Prescott S. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest 2011;139:640-647.

Figure 1 Development of asthma may be influenced by a number of different environmental exposures.

The complex network of asthma risk and protective factors

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Asthma is defined in the same way in children as in adults. However, there are many particularities that make childhood asthma a challeng-ing condition, including the rela-tive scarcity of evidence in this age group. Asthma starts early and per-sists, often for life, following a not completely defined pattern. Nat-ural history studies have shown that many children, who wheeze early in life overcome this problem later on. However, some of these patients relapse, while others de-velop asthma at different times in their lives (Figure 1). Severity and atopy are the elements most strongly associated to wheeze/asthma persistence. Asthma symp-toms coexist or follow other al-lergy-related conditions such as atopic dermatitis and/or rhinitis. In children, the “atopic march” has been used as a metaphor to charac-terize the longitudinal transforma-tion of such conditions in the same patient. Frequent comorbidities, especially rhinitis, should always be taken into account, when evalu-ating patients.

The clinical presentation of asthma in childhood is dynamic, evolving in parallel to the development of both the respiratory and the immune systems. Symptoms are typical, in-

cluding wheeze, cough, shortness of breath and chest tightness. Exac-erbations are frequent in children, usually precipitated by a common cold. In many cases, such exacer-bations are the only clinical expres-sion of the disease. However, it is becoming increasingly clear that asthma includes several different disease patterns, with distinct trig-gers, response to treatment and prognosis. Such phenotypes, which reflect similar diversity of mecha-nisms (endotypes), can be useful in disease management. Phenotypes have been related to epidemiolog-ical outcome, severity, or triggers; among the latter, the distinction between virus-induced asthma,

exercise-induced asthma and al-lergen-induced asthma, proposed by the Pediatric Asthma PRAC-TALL, may have practical implica-tions (Figure 2). Age is also crucial, with major differences in clinical presentations, depending both on physiological development, but also social characteristics, cogni-tive capacity and compliance.

The pathology and pathophysiolo-gy of childhood asthma share key elements of inflammation and re-modeling with adult asthma. How-ever, inflammation may not always be eosinophilic; in milder cases, inflammation appears during exac-erbations, in parallel to symptoms

Ke y m e ssag e s• Important differences exist between pediatric and adult asthma,

supporting the need for distinct management plans and guidelines• Pediatric asthma phenotypes, including virus-induced, exercise-

induced and allergen-induced asthma, highlight the complexity of the disease

• The diagnosis of asthma is difficult in early childhood• Pediatric asthma treatment is multifaceted (including education,

avoidance of triggers, pharmaceutical drugs and biological interventions) and dynamic (including monitoring, taking into account cost and geopolitical characteristics).

• Age and phenotype-specific characteristics of efficacy of different medications should be taken into account

ASTHMA IN CHILDHOOD19Nikolaos G. Papadopoulos

University of Athens Greece

Asthma in childhood

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and bronchoconstriction. Further-more, outside exacerbations, lung function is very often within the normal range. Remodeling is pres-ent in preschool children (Figure 3) to the same extent as older chil-dren and adults, but not yet pres-ent in infants.

The diagnosis of asthma can be challenging, particularly in young-er children. Asthma diagnosis is at best provisional in infants. In pre-school children a detailed history

and the exclusion of other wheez-ing disorders are mandatory and a well-designed therapeutic trial may help to establish the diagnosis. Lung function can be evaluated by impulse oscilometry. In school-age children and adolescents, evalu-ation of bronchial hyperrespon-siveness and airway inflammation offer additional information. At-opic sensitization should always be assessed, as it offers information both about possible triggers and prognosis.

Patient education, identification and avoidance of triggers, phar-macotherapy, immunotherapy and close monitoring are the corner-stones of treatment. Each of these has age-related particularities. Educational programs should be age-tailored; school programs can be very helpful. In early childhood, respiratory viruses are by far the most common disease triggers. With increasing age, allergen trig-gers become more clinically rele-vant.

Figure 1 Patterns of wheezing persistence among 6265 children

followed up longitudinally for 7 years (ALSPAC study). (Reproduced from Thorax,

Henderson J, Granell R, Heron J, et al, 63, 974-980, Copyright 2008, with permission

from BMJ Publishing Group.)

Figure 2 Asthma phenotypes in children aged >2 years of age. Phenotypes are a useful guide to the predominant problem and overlap between phenotypes is frequently present. *Children may also be atopic # Different etiologies, including

irritant exposure and as-yet not evident allergies may be included here. (Reproduced from Bacharier LB, Boner A, Carlsen KH, et al., Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy 2008;63:5-34, with permission from

Wiley-Blackwell.)

Virus-induced asthma*

Are coldsthe most common

precipitating factor?

Yes

Exercise-induced asthma*

Is exercise the mostcommon or only

precipitating factor?

Yes

Does the child haveclinically relevent

allergic sensitization?

No No

Allergen-induced asthma

Yes

Unresolved asthma*#

No

Yes No

Is the child completely wellbetween symptomatic periods?

Asthma in childhood

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Asthma in childhood

Pharmacotherapy follows a step-wise approach, based on disease control (Figure 4). Unfortunately, the volume of evidence on drug effectiveness in children is inad-equate, although it is clear that this differs from adults, or even between pediatric age groups. In-haled corticosteroids remain the cornerstone of long-term anti-in-flammatory treatment. Apparent differential responses to medica-tions are those to leukotriene re-ceptor antagonists and long-acting beta 2 agonists, the former being more and the latter less effective, as compared to adult studies.

Immunotherapy is currently the only treatment with disease-mod-ifying potential, for patients with allergen-induced asthma. Intensive

research is necessary to optimize this potential.

Close monitoring is essential. In-creased difficulty in compliance and use of devices, rapid changes in disease development and the need to monitor growth, add complexity to the management and underline the importance on regular moni-toring.

Strategies for primary prevention are still to be discovered, with the exception of smoking avoidance during pregnancy, which is strongly recommended.

KEY REFERENCES1. Papadopoulos NG, Arakawa H,

Carlsen KH, Custovic A, Gern J, Lemanske R, et al. International consensus on (ICON) pediatric

Figure 3 Bronchial bi-opsy from a 6-year old girl with severe persis-tent asthma. An intact but hyperplastic airway epithelium and markedly thickened basement mem-brane, with only minimal inflammation character-ized by patchy lymphocyt-ic infiltration immediately below the basement mem-

brane can be seen. (Reproduced with permission from the American College of Chest Physicians from Jenkins HA, Cool C, Szefler SJ, et al. Histopathology of severe childhood asthma: a case series. Chest 2003;124:32-41.)

Figure 4 The stepwise approach to asthma treatment in childhood aims at disease control. An easy way to memorize this stepwise approach is that the

number of each step suggests the number of medications, or ICS level, to be used. (Reproduced from Papadopoulos NG, Arakawa H, Carlsen KH, et al. International

consensus on (ICON) pediatric asthma. Allergy 2012;67: 976-997, with permission from Wiley-Blackwell.)

asthma. Allergy 2012;67: 976-997.

2. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Wood-cock A, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsive-ness in mid-childhood. Thorax 2008;63:974-980.

3. Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, Frischer T, Götz M, et al. Diagnosis and treat-ment of asthma in childhood: a PRACTALL consensus report. Al-lergy 2008;63:5-34.

4. Konstantinou GN, Xepapadaki P, Manousakis E, Makrinioti H, Kouloufakou-Gratsia K, Saxoni-Papageorgiou P, et al. Assessment of airflow limitation, airway inflammation, and symptoms during virus-induced wheezing episodes in 4- to 6-year-old children. J Allergy Clin Immunol 2013;131:87-93.e1-5.

5. Jenkins HA, Cool C, Szefler SJ, Co-var R, Brugman S, Gelfand EW, et al. Histopathology of severe child-hood asthma: a case series. Chest 2003;124:32-41.

6. Saglani S, Malmström K, Pelkonen AS, Malmberg LP, Lindahl H, Ka-josaari M, et al. Airway remodeling and inflammation in symptomatic infants with reversible airflow ob-struction. Am J Respir Crit Care Med 2005;171:722-727.

7. Eigenmann PA, Atanaskovic-Markovic M, O’B Hourihane J, Lack G, Lau S, Matricardi PM, et al. Testing children for allergies: why, how, who and when: An updated statement of the European Academy of Allergy and Clinical Immunology (EAACI) Section on Pediatrics and the EAACI-Clemens von Pirquet Foundation. Pediatr Allergy Immunol 2013;24:195-209.

8. Calderon MA, Demoly P, Gerth van Wijk R, Bousquet J, Sheikh A, Frew A, et al. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy. Clin Transl Allergy 2012;2:20.

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The population of the world is ag-ing, with the greatest increases occurring in those over 85 years of age. Twenty-five percent of the US population will be more than 65 years of age by 2050 (Figure 1). Asthma occurs in all adult age groups, both as a new diagnosis and as a condition that existed from a younger age. The preva-lence of asthma in the elderly is 4 to 13%, similar to younger adult populations, and the incidence is approximately 1/1000/year. How-ever, asthma is probably underdi-agnosed due to the attribution of symptoms and signs to diseases other than asthma in older popu-lations or acceptance of symptoms and limitations as the result of ag-ing. Compared to asthma begin-ning at a younger age, new onset asthma in older adults tends to be more severe and progressive, more likely in women and less reversible. The mortality of asthma increases with aging (Figure 2).

Aging influences the symptoms of asthma as well as the mortality. This may be due to changes in air-way physiology with aging and the decreased response to treatment. Lung function decreases with age due to increased stiffness of the chest wall, reduced respiratory

muscle function and an increase in residual volume from the loss of elastic recoil. The decline in the elasticity of the airway with age is major contributor to the increase in fixed airflow obstruction and work of breathing. The result is a decrease in FEV1/FVC, such that normal elders have spirometric features suggestive of obstructive lung disease. Thus, the diagnosis of asthma in the elderly is challeng-ing, and asthma in older adults is commonly misdiagnosed as chron-

ic obstructive lung disease disease (COPD), resulting in under-diagno-sis and under-treatment of asthma. Significant, irreversible airflow ob-struction in older adults is usually due to COPD, asthma with remod-eling or bronchiectasis with seg-mental fibrosis. Lung volume and diffusion capacity studies and high resolution tomographic imaging may be helpful in identifying dis-eases other than asthma in older adults with persistent dyspnea or FEV1 less than 60% of predicted.

Ke y m e ssag e s• Asthma in older adults is a result of both persistent disease and

new onset disease• Normal lung function in older subjects has features of airflow

obstruction, complicating the diagnosis of asthma and challenging the distinction between chronic obstructive lung disease and asthma

• Allergens and allergic sensitivity are less important compared to younger populations but allergy remains relevant in the elderly

• Treatment of asthma is not fundamentally different. Imunotherapy and environmental control are generally less effective, tolerance to inhaled corticosteroids and beta agonists is decreased, anticholinergic therapy may be a consideration due to fixed obstructive changes of aging

• Infections are an important cause of severe exacerbations. Vaccination status should be verified in older subjects with asthma

• Medication side effects are a greater challenge in the elderly

ASTHMA IN THE ELDERLY20Dennis K. Ledford

University of South Florida Tampa, USA

Asthma in the elderly

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Millions

65 and over

Projected

85 and over0

20

40

60

80

100

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050

NOTE: These projections are based on Census 2000 and are not consistent with the 2010 Census results. Projections based on the 2010 Census will be released in late 2012.Reference population: These data refer to the resident population.SOURCE: U.S. Census Bureau, 1900 to 1940, 1970, and 1980, U.S. Census Bureau, 1983, Table 42; 1950, U.S. Census Bureau, 1953, Table 38; 1960, U.S. Census Bureau, 1964, Table 155; 1990, U.S. Census Bureau, 1991, 1990 Summary Table File; 2000, U.S. Census Bureau, 2001, Census 2000 Summary File 1; U.S. Census Bureau, Table 1: Intercensal Estimates of the Resident Population by Sex and Age for the U.S.: April 1, 2000 to July 1, 2010 (US-EST00INT-01); U.S. Census Bureau, 2011. 2010 Census Summary File 1; U.S. Census Bureau, Table 2: Projections of the population by selected age groups and sex for the United States: 2010–2050 (NP2008-t2).

Figure 1 Population of United States, age 65 and over and age 85 and over, selected years 1900-2010 and projected 2020-2050. (From http://www.agingstats.gov/Main_Site/Data/2012_Documents/docs/Population.pdf, accessed May 20, 2013.)

0

1

2

3

4

5

6

7

8

9

10

0–14 15–24 25–34 35–44 45–54 55–64 65–74 ≥75

WhiteBlack

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per 1

00,0

00 p

opul

atio

n

Age group (yrs)

†

Figure 2 Asthma Death Rates by Race and Age, United States 2007-2009. (From Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, 2012;61:315.)

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Figure 3 Effect of age on state of inflammation. Mean values of inflammatory markers according to age and sex group expressed as number of standard deviations from the population mean to make the values independent of different units

of measure. (Republished with permission of Blood, from The origins of age-related proinflammatory state, Ferrucci L, Corsi A, Lauretani F, et al, 105, 6, 2005; permission conveyed through Copyright Clearance Center, Inc.)

Aging affects the immune system in various ways (Figures 3 and 4). Expected findings in the elderly are naïve T cells decrease with de-cline in ability to respond to new

antigens, memory T cells increase, CD8 suppressor/cytotoxic cells in-crease, B-cell function decreases, innate immune function decreases, neutrophil number increases and

eosinophil function is relatively un-changed. IgE production decreases with age, although some data do not support this point. However, wheal and flare skin test responses


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Figure 4 Immunosenescence and the potential effects on asthma. (Reprinted from J Allergy Clin Immunol, 126/4, Busse PJ, Mathur SK, Age related changes in immune function: effect on airway inflammation, 690-696, Copyright 2010, with permission

from Elsevier.)

in older asthmatics are predictive of symptoms but are less reliable in predicting response to allergen in-halation challenge than in younger populations. Allergic sensitization is more common in older adults with asthma than in age-matched controls without asthma, with studies of Caucasian populations showing 28-74% of older asthmat-ics sensitive to at least one antigen. However, subjects who develop asthma later in life are much less likely to have specific-IgE than younger subjects. Aging of skin de-creases the usefulness of skin test-ing in solar damaged skin. IL-6 in-creases with age and IL-6 inversely correlates with survival. IL-6 and associated noneosinophilic inflam-mation may affect the airway.

Asthma with onset after 40 years of age is rarely IgE mediated and

has much less familial linkage. The greater duration of asthma, the less likely lung function will be normal (Figure 5). Lung function decreases with age from the max-imum value at approximately 20 years of age. The average decrease in FEV1 is 25-30 ml/year, and this loss is accelerated in some by cig-arette smoke exposure or chronic asthma.

Management of asthma in the el-derly is no different than in young-er populations, except the medi-cations may be less effective and less tolerated. Inhaled medications require a sufficient airflow for powder devices or coordination for metered dose inhalers, possibly limiting effectiveness in the elder-ly. The dryness of oral and larynge-al mucosa in older subjects reduces the tolerance of inhaled corticos-

teroids, and older asthmatics may derive less benefit from inhaled corticosteroids. The tolerance to short or long acting beta agonists is another concern, and anticholiner-gic therapy, not approved in asth-ma but demonstrated to be effec-tive, may be a consideration. Due to low flow rates and small airway disease, oral therapy may be de-sirable with consideration of short courses of oral corticosteroids, low dose theophylline or a trial of leu-kotriene modifiers. Infections are a frequent cause of exacerbations and may result in severe exacer-bations requiring hospitalization. Therefore, vaccine recommen-dations include annual influenza vaccine, periodic pneumococcal vaccine and boosting of pertussis immunity once as an adult. Mon-itoring for side effects of therapy is very important in older subjects.

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Figure 5 Lung function as measured by FEV1 in patients with diagnosis of asthma made after the age of 65 years at a single referral clinic. (Reprinted from J Allergy Clin Immunol, 103/4, Reed CE, The natural history of asthma in adults: the problem

of irreversibility, pp 539-547, Copyright 1999, with permission from Elsevier.)

This monitoring includes serum potassium and glucose with in-haled beta agonists, particularly when combined with high dose in-haled corticosteroids or oral cor-ticosteroids, bone density when regular inhaled corticosteroids or recurrent systemic corticosteroids are required, monitoring serum 25-hydroxyvitamin D with target concentrations of 40-50 ng/ml, and assessment of strength to detect myopathy.

KEY REFERENCES1. Busse PJ, Mathur SK. Age related

changes in immune function: ef-fect on airway inflammation. J Al-lergy Clin Immunol 2010;126:690-696.

2. McHugh MK, Symanski E, Pom-peii LA, Delclos GL. Prevalence of asthma among adult females and males in the United States: Results from the National Health

and Nutrition Examination Survey (NHANES), 2001-2004. J Asthma 2009;46:759-766.

3. Stupka E, deShazo R. Asthma in seniors: Part 1. Evidence for un-derdiagnosis, undertreatment and increasing morbidity and mortali-ty. Am J Med 2009;122:6-11.

4. Reed C. Asthma in the elderly: Di-agnosis and management. J Allergy Clinic Immunol 2010;126:681-687.

5. Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, et al. The origins of age-related proinflammatory state. Blood 2005;105:2294-2299.

6. Busse PJ, Lurslurchachai L, Samp-son HA, Halm EA, Wisnivesky J. Perennial allergen-specific im-munoglobulin E levels among in-ner-city elderly asthmatics. J Asth-ma 2010;47:781-785.

7. Zureik M, Orehek J. Diagnosis and severity of asthma in the elderly: results of a large survey in 1,485

asthmatic recruited by lung spe-cialists. Respiration 2002;69:223-228.

8. King MJ, Lockey RF. Aller-gen prick-puncture skin test-ing in the elderly. Drugs Aging 2003;20:1011-1017.

9. Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalk-er M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198-1207.

10. Mai XM, Langhammer A, Camargo CA Jr, Chen Y. Serum 25-hydrox-yviatamine D levels and incident asthma in adults: The HUNT study. Am J Epidemiol 2012;176:1169-1176.

11. Bos IS, Gosens R, Zuidhof AB, Schaafsma D, Halayko AJ, Meurs H, et al. Inhibition of al-lergen-induced airway remode-ling by tiotroprium and budeso-nide: a comparison. Eur Respir J 2007;30:653-661.


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PREVALENCE OF ASTHMA IN THE ATHLETEThe prevalence of asthma, atopy, exercise-induced bronchocon-striction (EIB), and airway hyper-responsiveness (AHR) is increased in high-level athletes (Table 1). Asthma has been reported in 2.7 to 22.8% of summer sports athletes and from 2.8 to 54.8% of winter sports athletes, variations that may be related to the different athletes populations and diagnos-tic tests. The prevalence of AHR is even higher and varies from 25 to 79% in athletes performing endur-ance sports while it is around 20% in power and speed sports athletes.

MECHANISMS OF DEVELOPMENT OF ASTHMA AND RISK FACTORSThere are increasing evidences that high-intensity repeated exer-cise, particularly when the athlete is exposed to allergens, pollut-ants, chlorine derivatives or cold air during training, may promote the development of asthma and AHR (Figure 1). The mechanisms by which these agents could in-duce long-term changes in airway function in athletes are still to be determined but they seem to act through airways epithelial damage, inflammation - most often, neutro-

philic or paucigranulocytic - and remodelling. Frequent/intense air-way dehydration and mechanical airway stress from intense exercise may contribute to these changes.

CLINICAL FEATURES OF ASTHMA IN THE ATHLETERespiratory symptoms are un-reliable to make the diagnosis of asthma in athletes and objective tests demonstrating variable air-way obstruction and/or hyperres-ponsiveness such as methacholine or mannitol challenges, exercise

tests (field or laboratory) or eucap-nic voluntary hyperpnea test are needed.

MANAGEMENTThe optimal management of asth-ma in athletes includes general pharmacological and non-phar-macological measures suggested in current guidelines (Figure 2). Attention should be particularly paid to the prevention of EIB, the development of a tolerance to the bronchoprotective effects of in-haled β2-agonists and assessment

Ke y m e ssag e s• The prevalence of asthma and airway hyperresponsiveness is

increased in the athlete • Asthma presents as a specific phenotype in the athlete, with a less

eosinophilic airway inflammation, sometimes more difficult to control asthma and significant reversibility of changes in airway hyperresponsiveness (AHR) after cessation of training in sub-groups such as swimmers

• Environmental factors such as repeated inhalation of chlorine derivatives (in swimmers), cold air (in winter sports), allergens and pollutants are considered to play a role in the development of asthma and AHR in the athlete

• Asthma should be diagnosed early in athletes and preventative measures suggested to protect the airways and optimize performance

• Medication use should comply with the requirements of the World Anti-Doping Agency

ASTHMA IN THE ELITE ATHLETE21

Louis-Philippe Boulet Laval University Québec, Canada

Asthma in the elite athlete

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TABLE 1

Prevalence of physician-diagnosed asthma, exercise-induced bron-choconstriction and airway hyperresponsiveness in elite athletes

Type of sport PDA EIB AHR

Winter athletes 14-28% 23-35% 23-52%

Swimmers ≅8% --- 36-79%

Other endurance sports 2-20% 15-19% 9-21%

Adapted from Langdeau et al. Sports Med 2001. (PDA = Physician-diagnosed asthma; EIB = Exercise-induced bronchoconstriction; AHR = Airway hyperres-ponsiveness as measured in assessing response to methacholine or other agents)

Figure 1 Possible mechanisms of development of

asthma and airway hyperresponsiveness in

athletes.

of the benefits from asthma med-ications, as these last seem often less effective in high-level athletes to relieve respiratory symptoms (Table 2). The sometimes observed poorer global treatment response may be due to the fact that some respiratory symptoms are not due to asthma, but are associated with other co-morbid conditions (rhini-tis, gastro-esophageal reflux, vocal cord dysfunction) or to the intense exercise. It is also possible that ath-letes show a resistance to asthma drugs, possibly due to a predom-inant airway remodeling or more neutrophilic type of airway inflam-mation. Medication use should comply with the requirements of the World Anti-Doping Agency (http://www.wada-ama.org/en/, accessed May 20, 2013). Rhinitis is common in athletes and should be

also treated according to current guidelines.

PREVENTATIVE MEASURES AND LONG-TERM OUTCOMESPreventative measures include avoidance, whenever possible, of training during high-level exposure to allergens/ pollutants, extremely cold temperature and in improv-ing measures to reduce chlorine by-products levels in pools (Table 3).

Interestingly, there are evidences that airway responsiveness can, at least partly, normalize after stop-ping training. Further research is needed on how to reduce the risk of developing asthma and/or AHR in the athlete, how these last in-fluence athletes’ performance and what is their outcome after cessa-tion of training for various types of sports.

CONCLUSIONAsthma and AHR are common in the high-level athlete. Competitive endurance training may promote the development of asthma and AHR through various mechanisms. The diagnosis requires bronchop-rovocation tests and although the management of asthma should be similar to other type of asthmatic patients, specific environmental preventative measures and pre-vention of tolerance to β2 agonist should be ensured. Airway func-tion may partly or totally normal-ize after cessation of training but more research is needed on how to prevent the development of asth-ma and AHR in this population and what is their optimal pharmacolog-ical therapy.

KEY REFERENCES1. Helenius IJ, Tikkanen HO, Sarna S,

Haahtela T. Asthma and increased bronchial responsiveness in elite athletes: atopy and sport event as risk factors. J Allergy Clin Immunol 1998;101:646-652.

2. Langdeau JB, Turcotte H, Bowie DM, Jobin J, Desgagné P, Boulet LP. Airway hyperresponsiveness in elite athletes. Am J Respir Crit Care Med 2000;161:1479-1484.

3. Fitch KD, Sue-Chu M, Anderson SD, Boulet LP, Hancox RJ, Mc-Kenzie DC, et al. Asthma and the elite athlete: summary of the International Olympic Commit-tee’s consensus conference, Lau-sanne, Switzerland, January 22-24, 2008. J Allergy Clin Immunol 2008;122:254-260.

4. From the Global Strategy for Asthma Management and Pre-vention. Global Initiative for Asth-ma (GINA) 2012. Available from: www.ginasthma.org.

5. Bougault V, Turmel J, Boulet LP. Airway hyperresponsiveness in elite swimmers: Is it a transient phenomenon? J Allergy Clin Immu-nol. 2011;12:892-898.

Hyperventilation with airways heat and water loss,increased penetration of pollutants and allergens and mechanical + oxydative stress to the airways

Epithelial ‘damage’ with loss of protective mediators, microvascular leak/plasma

exsudation and trigger of a repair process

Changes of contractile properties of the airway smooth muscle, airway

remodelling ± Inflammation

Asymptomatic airway hyperresponsivess

Symptomatic asthma


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Figure 2 Asthma management for the athlete. BD - Bronchodilator; FVC - forced vital capacity; FEV1 - forced expiratory volume in the first second; WADA - World Anti Doping Agency. (Adapted from J Allergy Clin Immunol, 122/2, Fitch KD, Sue-

Chu M, Anderson SD, et al, Asthma and the elite athlete: summary of the International Olympic Committee’s consensus conference, Lausanne, Switzerland, January 22-24, 2008, 254-260, Copyright 2008, with permission from Elsevier.)

TABLE 2

Specific considerations about the management of asthma in the high-level athlete

• Difficulties in assessing « asthma-like symptoms »

• Should we treat what is considered asymptomatic AHR ?

• Unrecognized alterations in lung function due to high baseline values

• High level of exposure to sensitizer/irritants

• Undertreatment/Overtreatment

• Presence of confounding conditions (VCD, over-training, etc.)

• Reduced response to therapy

• Requirements by sports authorities

• Assessment of long-term outcomes

TABLE 3

Examples of preventative measures for asthmatic athletes

Avoidance of training during:

• high-level exposure to relevant allergens

• days of intense air pollution

• extremely cold temperature

Reduce chlorine by-products levels in pools

• personal bathers hygiene

• control of chlorine levels

• Improved ventilation of pool environment

Ensure adequate asthma control

Warm-up before exercising

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• Pregnant asthmatics have a higher risk of adverse perinatal outcomes

• Adherence to treatment, specifically inhaled corticosteroids, has been a problem and is usually due to concerns regarding the safety of these medications during pregnancy

• Pregnant asthmatics should be monitored on a monthly basis so that any change in course can be matched with an appropriate change in therapy

• Patient education is an important part of managing the pregnant asthmatic, which includes explaining the relationship between asthma and pregnancy, identifying asthma triggers, providing training on correct use of inhalers and establishing an asthma action plan

• One of the most important needs for the future is the availability of further safety information for asthma medications used during pregnancy that can also account for asthma control

Asthma is the most common po-tentially serious chronic medical condition to affect pregnancy, with a prevalence of self-reported asthma in the United States be-tween 8.4 and 8.8%. A meta-anal-ysis, derived from a substantial body of literature spanning several decades and including very large numbers of pregnant women, (over 1,000,000 for low birth weight and over 250,000 for preterm labor), indicates that pregnant women with asthma are at a significantly increased risk of a range of adverse maternal and fetal outcomes (Table 1 and 2).

Mechanisms postulated to ex-plain the increased perinatal risks in pregnant asthmatic women demonstrated in previous studies have included hypoxia and other physiologic consequences of poor-ly controlled asthma, medications used to treat asthma, and patho-genic or demographic factors asso-ciated with asthma but not actually caused by the disease or its treat-ment, such as abnormal placental function. There are data to show that suboptimal control of asth-ma or more severe asthma during pregnancy is associated with in-creased maternal or fetal risk.

Asthma may worsen, improve, or

remain unchanged during preg-nancy, and the overall data suggest that these various courses occur with approximately equal frequen-cy. Asthma is likely to be more severe or to worsen during preg-nancy in women with more severe asthma before becoming pregnant.

The mechanisms responsible for the altered asthma course dur-ing pregnancy are unknown. The myriad of pregnancy-associated changes in levels of sex hormones, cortisol and prostaglandins may

contribute to changes in asthma course during pregnancy. In addi-tion, exposure to fetal antigens, leading to alterations in immune function may predispose some pregnant asthmatics to worsening of asthma. Even fetal sex may play a role, with some data showing in-creased severity of symptoms in pregnancies with a female fetus.

Once the diagnosis of asthma is confirmed (Table 3), a decision re-garding the need for controller medication versus rescue medica-

ASTHMA IN PREGNANCY22

Ke y m e ssag e s

Jennifer A. Namazy Scripps Clinic

San Diego, USA

Michael Schatz Kaiser Permanente Medical Center

San Diego, USA

Asthma in pregnancy

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Asthma in pregnancy

TABLE 2

Adverse fetal outcomes reported to be increased in infants of asthmatic women

• Low birth weight

• Preterm birth

• Small for gestational age

• Congenital anomalies

• Stillbirth

• Low APGAR scores at birth

TABLE 3

Differential diagnosis of dyspnea during pregnancy

• Asthma

• Dyspnea of pregnancy

• Reflux esophagitis

• Post nasal drainage

• Bronchitis

• Laryngeal dysfunction

• Hyperventilation

• Pulmonary edema

• Pulmonary embolism

tion can be made (Table 4). Inhaled corticosteroids are the mainstay of controller therapy during preg-nancy. Because it has the most published human gestational safe-ty data, budesonide is considered the preferred ICS for asthma dur-ing pregnancy. That is not to say that the other ICS preparations are unsafe. Therefore, ICS other than budesonide may be continued in patients who were well controlled by these agents prior to pregnan-cy, especially if it is thought that changing formulations may jeop-ardize asthma control. Controller therapy should be increased in steps (Table 5) until adequate con-trol is achieved.

Adherence to therapy can change during pregnancy with a corre-sponding change in asthma control. Most commonly observed is de-creased adherence as a result of a mother’s concerns about the safe-ty of medications for the fetus. For example, one study found that less than 40% of women who classified themselves as “poorly controlled” reported use of a controller medi-cation during pregnancy.

Patient education is an important part of the management of the pregnant asthmatic. Each patient should be provided basic informa-tion about asthma and the relation-ship between asthma and pregnan-cy. Monthly visits to assess asthma control and adherence are recom-mended for women who require controller therapy during pregnan-cy. Each patient should also receive a self-treatment action plan that includes how to recognize a severe exacerbation and when to seek ur-gent or emergency care (Table 6).

KEY REFERENCES1. Kwon HL, Belanger K, Bracken

MB. Asthma prevalence among pregnant and childbearing-aged

TABLE 1

Adverse maternal outcomes reported to be increased in pregnant asthmatic women

• Abortion

• Hyperemesis gravidarum

• Gestational diabetes

• Chorioamnionitis

• Pregnancy-induced hyperten-sion or preeclampsia

• Antepartum hemorrhage

• Placental complications

• Preterm labor

• Complicated labor

• Cesarean section

• Preterm birth

• Post-partum hemorrhage

women in the United States: es-timates from national health sur-veys. Ann Epidemiol 2003;13:317-324.

2. Namazy JA, Murphy VE, Powell H, Gibson PG, Chambers C, Schatz M. Effects of asthma severity, exacer-bations and oral corticosteroids on perinatal outcomes. Eur Respir J 2012;[Epub ahead of print].

3. Belanger K, Hellenbrand ME, Hol-ford TR, Bracken M. Effect of preg-nancy on maternal asthma symp-toms and medication use. Obstet Gynecol 2010;115:559-567.

4. Gluck JC, Gluck PA. The effect of pregnancy on the course of asth-ma. Immunol Allergy Clin N Am 2006;26:63-80.

5. Murphy VE, Gibson PG, Smith R, Clifton VL. Asthma during preg-nancy: mechanisms and treat-ment implications. Eur Respir J 2005;25:731-750.

6. Louik C, Schatz M, Hernán-dez-Díaz S, Werler MM, Mitch-ell AA. Asthma in pregnancy and its pharmacologic treatment. Ann Allergy Asthma Immunol 2010;105:110-117.

7. Namazy JA, Schatz M. Current guidelines for the management of asthma during pregnancy. Immunol Allergy Clin North Am 2006;26:93-102.

8. Namazy JA, Schatz M. Treatment of asthma during pregnancy and perinatal outcomes. Curr Opin Allergy Clin Immunol 2005;5:229-233.

9. Tegethoff M, Greene N, Olsen J, Schaffner E, Meinlschmidt G. Inhaled glucocorticoids during pregnancy and offspring pedi-atric diseases: a national cohort study. Am J Respir Crit Care Med 2012;185:557-563.

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TABLE 4

Safety of commonly used medications for the treatment of asthma during pregnancy *

Drug FDA Perinatal Outcome

Inhaled BronchodilatorsShort-acting Bronchodilators

Albuterol(C) Reassuring human data; some associations with specific malformations, but may be chance or confounding by severity

Long-acting bronchodilators Formoterol(C)Salmeterol(C)

Minimal human data has been reassuring

Theophylline No increase in congenital malformations ; toxicity may be an issue

Inhaled Corticosteroids Budesonide (B)Beclomethasone (C)Fluticasone (C)Mometasone (C)Triamcinolone (C)

Substantial reassuring data. Risk of increased malformations with high dose, but may be confounding by severity. Most data for budesonide.

Leukotriene Receptor Antagonists

Montelukast (B)Zafirlukast (B)

Moderate amount of reassuring data

5-LO Inhibitors Zileuton (C) Animal studies not reassuring

Anti-IgE Xolair (B) Risk of low birth weight and preterm birth, but may be confounding by severity

* Adapted from Schatz M, Zeiger RS, Falkoff R, et al. Asthma and allergic diseases during pregnancy. In: Adkinson, NF, Yunginger, JW, Busse, WW, et al, editors. Middleton’ s Allergy: Principles and Practice, 8 th edition. St. Louis, MO: Mosby, 2013 with permission from

Elsevier.TABLE 5

Steps of asthma therapy during pregnancy *

Step Preferred Controller Medication Alternative Controller Medication

1 None -

2 Low dose ICS LTRA, theophylline

3 Medium dose ICS Low dose ICS + either LABA, LTRA or theophylline

4 Medium dose ICS + LABA Medium dose ICS + LTRA or theophylline

5 High dose ICS + LABA -

6 High dose ICS + LABA + oral prednisone -

ICS = inhaled corticosteroids; LTRA – leukotriene-receptor antagonists; LABA = long-acting beta agonists*From N Engl J Med, Schatz M, Dombrowski MP, Clinical practice. Asthma in pregnancy, 360, 1862-1869 Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

TABLE 6

Patient education for self-management of asthma during pregnancy *

Subject Recommendation

General Information Provide basic information about asthma and relationship between asthma and pregnancyUse of inhaler device

Demonstrate proper technique for specific device and ask patient to perform the technique; demonstrate use of spacer device for metered-dose inhaler if patient’s technique is suboptimal

Adherence to treatment

Discuss self-reported adherence to treatment with controller medication and, if needed, address barriers to optimal adherence (e.g. cost, convenience, concern about side effects)

Self-treatment action plan

Provide schedule for maintenance medication and doses of rescue therapy for increased symptoms; explain when and how to increase controller medication and when and how to use prednisone(for patients with previous prednisone use or poorly controlled asthma); explain how to recognize a severe exacerbation and when and how to seek urgent or emergency care

*From N Engl J Med, Schatz M, Dombrowski MP, Clinical practice. Asthma in pregnancy, 360, 1862-1869 Copyright © 2009 Massa-chusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Asthma in pregnancy

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DEFINITIONS AND EPIDEMIOLOGYWork-related asthma comprises two major entities (Figure 1): oc-cupational asthma (OA), defined as a type of asthma caused by the workplace and work-exacerbated asthma (WEA), which refers to the worsening of asthma triggered by various work-related factors (e.g., irritants, aeroallergens, or exer-cise) in workers who are known to have pre-existing or concurrent asthma.

There are two major forms of OA:

• Allergic OA characterised by a latency period required for de-veloping sensitisation prior to the development of symptoms.

• Non-allergic irritant-induced OA characterised by the onset of asthma following single (i.e. reactive airways dysfunction syndrome, RADS) or multiple exposures to high concentra-tions of irritant agents.

A significant excess asthma risk has been observed after exposure to substances known to cause OA. OA is the most common oc-cupational lung disease in indus-trialised countries and the second most common work-related lung disease reported after pneumo-

conioses in developing countries. In a large longitudinal study, the population-attributable risk for adult asthma due to occupation-al exposures ranged from 10% to 25%, equivalent to an incidence of new-onset asthma of 250–300 cases per million people per year.

ETIOLOGY More than 400 agents encoun-tered at work have been reported to induce OA. These agents are categorized into high-molecu-lar weight (HMW) compounds, which are proteins acting through

an IgE-mediated mechanism, and low-molecular weight (LMW) compounds (<1000 Da), which are chemical sensitizers that, with few exceptions, are not associated with an IgE-dependent mechanism. Ta-ble 1 shows common causal agents of allergic OA. A more comprehen-sive list of etiologic agents can be found at: http://www.eaaci.org/sections-a-igs/ig-on-occupation-al-allergy/allergen-list.html and http://www.asthme.csst.qc.ca/doc-ument/Info_Gen/AgenProf/Bern-stein/BernsteinAng.htm (accessed May 20, 2013).

Ke y m e ssag e s• Occupational exposures are a significant contributor to the

burden of asthma• Work-related asthma can be classified into occupational asthma

(OA) and work-exacerbated asthma• OA is usually due to an allergic response to high or low-molecular

weight agents. Less commonly OA can result from high-level irritant exposures at work

• The cornerstone for the diagnosis of OA is evidence of a causal relationship between exposure to the offending agent, clinical symptoms and changes in lung function

• In the evaluation of OA appropriate clinical, immunological and environmental investigations should be carried out in a stepwise fashion

• The appropriate management remains early removal from exposure with preservation of income

WORK-RELATED ASTHMA 23Santiago Quirce

Hospital La Paz Institute for Health Research, Madrid, Spain

Enrico Heffler University of Torino

Italy

Work-related asthma

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Figure 1 Classification of work-related asthma. RADS - Reactive Airways Disfunction Syndrome.

(Reproduced from Moscato G, Pala G, Barnig C, et al. European Academy of

Allergy and Clinical Immunology. EAACI consensus statement for investigation of work-related asthma in non-specialized centres. Allergy 2012;67:491-501, with

permission from Wiley-Blackwell.)

Bakers and pastry makers, spray painters, cleaners and healthcare workers are the occupations con-sistently associated with a higher incidence of OA. The main causes of OA include isocyanates, cereal flour/grain dust, welding fumes and wood dust.

NATURAL HISTORY AND RISK FACTORSOA is the result of an interaction between multiple genetic, environ-mental, and behavioral influences. Rhinoconjunctivitis often precedes the onset of IgE-mediated OA and it should be considered an impor-

tant risk factor for OA.

Although many factors influence the host response after exposure to workplace agents, four deter-minants have received particular attention: level of exposure (the higher the exposure, the greater

TABLE 1

Common specific agents and jobs associated with allergic occupational asthma

Causal agents Selected jobs or industries

High-molecular weight compounds

Cereals and flour Bakers and pastry makers, grain handlers

Animal epithelia, hairs, secretions Farmers, livestock workers, veterinaries

Seafood and other food-derived proteins Food processors, cooks, butchers

Latex proteins Healthcare and social workers

Enzymes (from bacterial, fungal and plant origin) Detergent industry workers, researchers, bakers, food technology

Vegetal gums Printing, food industry, carpet manufacture

Insects, mites Farmers, greenhouse workers, researchers

Low-molecular weight compounds

Isocyanates Spray painters, lacquerers, foam workers

Metals (e.g. platinum, nickel sulfate) Alloy and refinery workers, electroplating

Persulfate salts Hairdressers

Acrylates (methacrylate, cyanoacrylate) Glue handlers, dentists, artificial nail workers

Aldehydes (e.g. glutaraldehyde) Hospital and laboratory workers

Acid anhydrides (e.g. trymellitic anh.) Plastics industry, eposy resins workers

Amines (e.g. ethanolamine) Metal workers (cutting fluids), various

Soldering flux (colophony) Welders

Mixed or uncertain relevant compounds

Wood dust (red cedar, iroko, obeche, etc) Woodworkers, carpenters, sawmill workers

WORK-RELATED ASTHMA

Asthma caused by work=

OCCUPATIONAL ASTHMA (OA)

Asthma exacerbated by work=

WORK-EXACERBATED ASTHMA (WEA)

ALLERGIC OA• IgE dependent

• Non IgE dependent

NON ALLERGICIRRITANT-INDUCED OA

Single exposure=

RADS

Multiple exposures=

IRRITANT INDUCED OA AFTER MULTIPLE EXPOSURES

Work-related asthma

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Work-related asthma

Figure 2 Stepwise approach for the clinical investigation of suspected work-related asthma. (PEF - peak expiratory flow; BHR - bronchial

hyperresponsiveness to methacholine/histamine).

the risk); atopy, which is consid-ered a risk factor for IgE-mediat-ed sensitization to HMW agents, although atopy itself is a weak predictor of development of OA; cigarette smoking (shown to be a risk factor for the development of specific IgE antibodies against occupational agents, although not necessarily for asthma); and genet-ic predisposition.

DIAGNOSISThe primary goal for diagnosing OA is to demonstrate a causal re-lation between exposure to a spe-cific agent encountered at work and asthmatic responses. Facts that reinforce the suspicion of work-relatedness of asthma are summarized in Table 2. A stepwise approach is often used (Figure 2). The advantages and disavantages of the different diagnostic meth-ods are shown in Table 3.

Specific inhalation challenge tests have been proposed as the gold standard in the diagnosis of OA. Evaluation of airway inflammation using non-invasive methods such as exhaled nitric oxide and induced

sputum to assess inflammatory cells and soluble markers of cell ac-tivation can be used as an adjunct to making the diagnosis of OA.

MANAGEMENT AND PROGNOSISThe likelihood of improvement or resolution of symptoms or of pre-venting deterioration is greater in workers who have no further expo-sure to the causal agent, in workers who have relatively normal lung function at the time of diagnosis, and in workers who have short-er duration of symptoms prior to diagnosis or prior to avoidance of exposure. Thus, early diagno-sis and early avoidance of further exposure are the cornerstones of patient management for patients with allergic OA (Table 4). When-ever feasible the patient should be relocated to a job category with-out exposure. For patients with irritant-induced asthma, however, they usually may keep working in the same job, provided measures are taken to prevent further expo-sures to high concentrations of irri-tant agents.

KEY REFERENCES1. Tarlo SM, Balmes J, Balkissoon R,

Beach J, Beckett W, Bernstein D, et al. Diagnosis and management of work-related asthma: Ameri-can College of Chest Physicians Consensus Statement. Chest 2008;134:1S-41S.

2. Moscato G, Pala G, Barnig C, De Blay F, Del Giacco SR, Folletti I, et al. European Academy of Allergy and Clinical Immunology. EAACI consensus statement for investi-gation of work-related asthma in non-specialized centres. Allergy 2012;67:491-501.

3. Kogevinas M, Zock JP, Jarvis D, Kromhout H, Lillienberg L, Plana E, et al. Exposure to substances in the workplace and new-onset asthma: an international pro-spective population-based study (ECRHS-II). Lancet 2007;370:336-341.

4. Jeebhay MF, Quirce S. Occupa-tional asthma in the developing and industrialised world: a review. Int J Tuberc Lung Dis 2007;11:122-133.

5. Malo JL, Chan-Yeung M. Agents causing occupational asthma. J Al-lergy Clin Immunol 2009;123:545-550.

6. Quirce S. Occupational asthma. In: Polosa R, Papale G, Holgate ST, editors. Advances in Asthma Man-agement. London: Future Medi-cine Ltd, 2012; 88-102.

7. Vandenplas O, Dressel H, Nowak D, Jamart J. ERS Task Force on the Management of Work-relat-ed Asthma. What is the optimal management option for occu-pational asthma? Eur Respir Rev 2012;21:97-104.

Comprehensive clinical and occupational/environmental historyAssociated disorders?: rhinitis, urticaria, dermatitis, food allergy

Asthma diagnosis:- Reversible airflow limitation- Bronchial hyperresponsiveness to methacholine

Immunologic assessment:- Skin prick testing and/or specific IgE tests - Immunoblotting, microarrays

Serial PEF measurements at/off workSerial measurements of BHR

Specific inhalation challenges:identification of the culprit agents

Special

ized ce

nters

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TABLE 2

Facts that reinforce the suspicion of work-relatedness of asthma *

• Recognition of high-risk jobs and/or exposure to known sensitizers

• Co-existence of allergic symptoms on other organs: rhinitis, conjunctivitis, contact urticaria

• Other coworkers affected

• Special events related with symptoms onset (new products used, new tasks, change in work practices, accidental ex-posures)

• Absence of response to conventional asthma therapy

• Personal risk factors (atopy, rhinitis, genetic background)

* Reproduced from Quirce S. Occupational asthma. In: Polosa R, Papale G, Holgate ST, editoris. Advances in Asthma Management. London: Future Medicine Ltd, 2012; 88-102.

TABLE 3

Advantages and disadvantages of diagnostic methods for occupational asthma *

Method Advantages Disadvantages

Clinical history Simple, sensitive Low specificity

Immunologic testing Simple, sensitive Valid only for some agents; identifies sensitization not disease;lack of standardized extracts

Bronchial responsiveness to methacholine

Simple, sensitiveNot specific for asthma or OA; OA not ruled our by a negative test

Serial PEF monitoring at work and off work

Relatively simple, affordableDepends on patients’ cooperation;no standardized interpretation

Specific inhalation challenge in the laboratory

If positive, confirmatoryIf negative, diagnosis not ruled out; few specialized centers; sophisticated equipment

Workplace challenge If negative under usual work conditions rules out diagnosis

A positive test may be due to irritation; requires collaboration (worker and employer)

Biomarkers of airway inflammation

Assess inflammation,specificity of reaction

Different types of inflammation;research tool, not validated

* Reproduced from Quirce S. Occupational asthma. In: Polosa R, Papale G, Holgate ST, editoris. Advances in Asthma Management. London: Future Medicine Ltd, 2012; 88-102.

TABLE 4

Management of occupational asthma

1. Work exposure

• For sensitizer-induced occupational asthma, avoid any further exposure to causative agents. If this is not possible, then reduce exposure as low as possible

• For irritant-induced occupational asthma avoid further high level exposure

2. Asthma treatment according to asthma guidelines

• Assessment of asthma control and severity

• Optimal pharmacotherapy, consider allergen immunotherapy

• Avoidance of asthma triggers, environmental control

• Patient’s education

3. Assist patient with relevant compensation claim and rehabilitation

4. Consider other co-workers affected and notify public health and company

Work-related asthma

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• The goal of asthma management is to achieve clinical control of the disease and of its risks

• Management of asthma requires a close partnership between patients and healthcare professionals

• Educational plans are important for self-management of asthma• Prevention and avoidance of risk factors that may precipitate

asthma are key elements of asthma management• Regular treatment is recommended• Asthma management should be adapted to every patient to

maintain asthma control with the minimum dose of medication• Asthma control should be assessed at regular intervals and

treatment level should be adjusted accordingly

Asthma is a chronic inflammatory disease of the airways character-ized by recurrent episodes of symp-toms such as dyspnea, wheezing, chest tightness and/or cough. Ac-cording to international guidelines the ultimate goal of asthma man-agement is to achieve control of the disease in terms of symptoms, pulmonary function, prevention of asthma exacerbations while avoid-ing adverse effects from asthma medications. Although effective medications are available, asthma remains substantially poorly con-trolled in real life. The reasons are diverse, partially related to inade-quate diagnosis or treatments or to low adherence to the prescribed inhalation treatment.

Solid partnership between pa-tients and physicians/health care professionals is crucial to attain ef-ficacious asthma management. Ed-ucational plans for patients play a major role in this partnership (Fig-ure 1). Patients must be informed about the disease, how to prevent, treat and keep asthma under con-trol. Tools for guided self-manage-ment such as written action plans developed with the health care professional should be provided, asthma control regularly assessed and treatment reviewed at regular

intervals (Figure 2).

Asthma exacerbations are crucial events in the natural history of the disease. They are defined as a sudden and/or progressive wors-ening of asthmatic symptoms and may occur even in patients under regular treatment. Preventing risk factors could improve asthma control, reduce asthma exacerba-tions and treatment requirements. Thus, asthmatic patients should not smoke, avoid exposure to sec-ond hand smoke and reduce where possible, exposure to domestic allergens and occupational sensi-tizers. Foods, additives and drugs known to worsen asthma symp-

toms should be avoided. Since viral infections are the most frequent cause of asthma exacerbations, pa-tients should be advised to receive influenza vaccination every year. Rhinitis, polyposis and sinusitis are comorbidities favoring poor asth-ma control; thus they should be ad-equately treated. Since pregnancy can undermine the control of the disease, pregnant women must be educated on the importance of ad-equate treatment during pregnan-cy for their own safety and for the safety for their babies. Asthma in obese asthmatics is often difficult to control. Weight loss should be pursued to improve asthma control (Figure 3).

ASTHMA MANAGEMENT24

Ke y m e ssag e s

Brunilda Marku Alberto Papi University of Ferrara

Italy

Asthma management

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Medications for asthma are classified as controllers (to be taken on regular basis) and relievers (they provide rapid relief of asthma symptoms). They are administered by inhalation: this is an effective way to reach the airways and to limit systemic side effects. The main controller medications are inhaled corticosteroids that switch-off the inflammation of asthmatic airways; long acting bronchodilators (β2 agonists) can be added when asthma is not adequately controlled. Other secondary controller medications include antileukotriens, theophylline or anti-IgE monoclonal antibodies in selected patients with severe allergic asthma (Figure 4).

Reliever medications (β2 fast act-ing agonists) are prescribed in every step of asthma severity. They have the ability to obtain a rapid bronchodilation in a very short time. A frequent use of reliever medication is a marker of poor con-trolled asthma.

Asthma is “controlled” when pa-tients have no clinical symptoms such as day time symptoms (or less than twice/week) and/or nocturnal symptoms/ awakening for asthma, no limitation of their daily activi-ties, no need use for the reliever medication (or less than twice/week) and have a normal lung func-tion (in terms of FEV1 or PEF) for over 4 weeks (Figure 5). Asthma treatment should be adjusted ac-cording to the level of asthma con-trol and stepped-up until good con-trol is achieved. Treatment should be stepped down when asthma control is stable and maintained for more than 3 months. Step-up and step-down should be adapted to every patient in order to maintain asthma control with the minimum dose of medication (Figure 6).

Figure 1 The circle of influence on management of asthma. Each ring represents people from family involvement, school or work, organizations, business practices and programs that turn around the patient represented at the center of the circle. (Reproduced with permission from the American College of Chest Physicians from Clark NM, Partridge MR. Strengthening asthma education to enhance disease control. Chest

2002;121:1661-1669.)

Figure 2 Example of an written action plan developed with the health care professional for self-management of

asthma by the patient. (Reproduced from the Global Strategy for Asthma Management

and Prevention, 2012 with permission of Global Initiative for Asthma (GINA)).

Patient Management

of asthma

Family Involvement

Clinical Expertise

Work/School Support

Community Awarences and Action

Community-Wide Environmental Measures

Conduit Policies

Effective Business Practices

Asthma management

Figure 4.1-3 Example of Contents of Written AsthmaAction Plan to Maintain Asthma Control

Your Regular Treatment:1. Each day take ___________________________2. Before exercise, take _____________________

WHEN TO INCREASE TREATMENTAssess your level of Asthma ControlIn the past week have you had:

Daytime asthma symptoms more than 2 times ? No YesActivity or exercise limited by asthma? No YesWaking at night because of asthma? No YesThe need to use your [rescue medication] more than 2 times? No YesIf you are monitoring peak flow, peak flow less than______? No Yes

if you answered YeS to three or more of these questions, your asthma isuncontrolled and you may need to step up your treatment.

HOW TO INCREASE TREATMENTSTEP-UP your treatment as follows and assess improvement every day:_________________________________ [Write in next treatment step here] Maintain this treatment for _____________ days [specify number]

WHEN TO CALL THE DOCTOR/CLINIC.Call your doctor/clinic: _______________ [provide phone numbers]If you don’t respond in _________ days [specify number]____________________________ [optional lines for additional instruction]

EMERGENCY/SEVERE LOSS OF CONTROL3If you have severe shortness of breath, and can only speak in short sentences,3 If you are having a severe attack of asthma and are frightened,3 If you need your reliever medication more than every 4 hours and are not

improving.1. Take 2 to 4 puffs ___________ [reliever medication] 2. Take ____mg of ____________ [oral glucocorticosteroid]3. Seek medical help: Go to ________________; Address______________

Phone: _______________________4. Continue to use your _________[reliever medication] until you are able

to get medical help.

Asthma exacerbations should be treated by increasing the use of reliever medication and may require administration of systemic corticosteroids until improvement of symptoms is obtained. Less frequently se-vere exacerbations may lead to hospital admission, oxygen supplementation and mechan-ical ventilation.

KEY REFERENCES1. From the Global Strategy for

Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2012. Available from: www.ginasth-ma.org.

2. Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, Weiss ST. World-wide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol 2004;114:40-47.

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Asthma management

Figure 3 Risk factors for asthma exacerbations and/or poor

control.

Figure 4 Treatment steps on asthma. Asthma medications are divided in relievers and controllers. The reliever medications must be prescribed in each step. The main controller medications are inhaled corticosteroids; long acting

bronchodilators (β2 agonists) can be added when asthma is not adequately controlled. When patients are not controlled with optimal doses of inhaled glucocorticoids in combination with long acting β2 agonists other adjunctive secondary

controller medications might be considered. (Reproduced from the Global Strategy for Asthma Management and Prevention, 2012 with permission of Global Initiative for Asthma (GINA)).

ASTHMA MANAGEMENT AND PREVENTION 67

Management Approach Based On ControlFor Children Older Than 5 Years, Adolescents and Adults

Controlleroptions***

* ICS = inhaled glucocorticosteroids**= Receptor antagonist or synthesis inhibitors *** = Preferred controller options are shown in shaded boxes

Treatment StepsAs needed rapid-acting β2-agonistAs needed rapid-acting β2-agonistLow-dose ICS pluslong-acting β2-agonistSelect one

Leukotrienemodifier**Select oneMedium-orhigh-dose ICSMedium-or high-doseICS plus long-actingβ2-agonistLow-dose ICS plusleukotriene modifierLow-dose ICS plussustained releasetheophylline

To Step 3 treatment,select one or more To Step 4 treatment,add eitherAsthma educationEnvironmental control

Low-dose inhaledICS* Oral glucocorticosteroid(lowest dose)Anti-IgEtreatmentLeukotrienemodifierSustained releasetheophylline

ControlledMaintain and find lowest controlling stepPartly controlledConsider stepping up to gain controlUncontrolledStep up until controlledExacerbationTreat as exacerbation

Treatment ActionLevel of ControlReduce

Reduce IncreaseI nc re ase

2Step1Step 3Step 4Step 5Step



* ICS = inhaled glucocorticosteroids**= Receptor antagonist or synthesis inhibitors

Treatment Steps

As needed rapid-acting β2-agonist As needed rapid-acting β2-agonist

Low-dose ICS pluslong-acting β2-agonist

Select one

Leukotrienemodifier**

Select one

Medium-orhigh-dose ICS

Medium-or high-doseICS plus long-acting

β2-agonist

Low-dose ICS plusleukotriene modifier

Low-dose ICS plussustained release

theophylline

To Step 3 treatment,select one or more

To Step 4 treatment,add either

Asthma education. Environmental control.(If step-up treatment is being considered for poor symptom control, first check inhaler technique, check adherence, and confirm symptoms are due to asthma.)

Low-dose inhaledICS*

Oral glucocorticosteroid(lowest dose)

Anti-IgEtreatment

Leukotrienemodifier

Sustained releasetheophylline

Controlled Maintain and find lowest controlling step

Partly controlled Consider stepping up to gain control

Uncontrolled Step up until controlled

Exacerbation Treat as exacerbation

Treatment ActionLevel of Control

Red

uce

Reduce Increase

Incr

ease


*** = Recommended treatment (shaded boxes) based on group mean data. Individual patient needs, preferences, and circumstances (including costs) should be considered.

Figure 4.3-2.

For management of asthma in children 5 years and younger, refer to the Global Strategy for the Diagnosis and Management of Asthma in Children 5 Years and Younger, available at http://www.ginasthma.org.

Alternative reliever treatments include inhaled anticholinergics, short-acting oral β2-agonists, some long-acting β2-agonists, and short-acting theophylline.Regular dosing with short and long-acting β2-agonists is not advised unless accompanied by regular use of an inhaled glucocorticorsteriod.

Strongodors

Stress and emotions

Exercise

Temperature change

Viral/bacterialrespiratory infections Allergens

Foodaditives

Gastroesophageal reflux

Rhinitis

DrugsSmoke

Obesity

Airpollution

Prevent risk factors

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Figure 5 Levels of asthma control evaluating daytime and nocturnal symptoms, limitation of activities, needs for reliever medication, lung function and exacerbation. (Reproduced from the Global Strategy for Asthma Management and Prevention,

2012 with permission of Global Initiative for Asthma (GINA)).

Figure 6 Step up and step down of treatment should be adapted to every patient in order to maintain asthma control with the minimum dose of medication. (Reproduced from the Global Strategy for Asthma Management and Prevention, 2012 with

permission of Global Initiative for Asthma (GINA)).

Asthma management

Figure 2-4. LEVELS OF ASTHMA CONTROL

A. Assessment of current clinical control (preferably over 4 weeks)

Characteristic Controlled (All of the following)

Partly Controlled(Any measure present)

Uncontrolled

Daytime symptoms None (twice or less/week)

More than twice/week Three or more features of partly controlled asthma*†

Limitation of activities None Any

Nocturnal symptoms/awakening

None Any

Need for reliever/ rescue treatment

None (twice or less/week)

More than twice/week

Lung function (PEF or FEV1)‡

Normal <80% predicted or personal best (if known)

B. Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side-effects)

Features that are associated with increased risk of adverse events in the future include:Poor clinical control, frequent exacerbations in past year*, ever admission to critical care for asthma, low FEV1, exposure to cigarette smoke, high dose medications

* Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate† By definition, an exacerbation in any week makes that an uncontrolled asthma week‡ Without administration of bronchodilator. Lung function is not a reliable test for children 5 years and younger

ASTHMA MANAGEMENT AND PREVENTION 67



* ICS = inhaled glucocorticosteroids**= Receptor antagonist or synthesis inhibitors *** = Preferred controller options are shown in shaded boxes

Treatment StepsAs needed rapid-acting β2-agonistAs needed rapid-acting β2-agonistLow-dose ICS pluslong-acting β2-agonistSelect one

Leukotrienemodifier**Select oneMedium-orhigh-dose ICSMedium-or high-doseICS plus long-actingβ2-agonistLow-dose ICS plusleukotriene modifierLow-dose ICS plussustained releasetheophylline

To Step 3 treatment,select one or more To Step 4 treatment,add eitherAsthma educationEnvironmental control

Low-dose inhaledICS* Oral glucocorticosteroid(lowest dose)Anti-IgEtreatmentLeukotrienemodifierSustained releasetheophylline

ControlledMaintain and find lowest controlling stepPartly controlledConsider stepping up to gain controlUncontrolledStep up until controlledExacerbationTreat as exacerbation

Treatment ActionLevel of ControlReduce

Reduce IncreaseI nc re ase




* ICS = inhaled glucocorticosteroids**= Receptor antagonist or synthesis inhibitors

Treatment Steps

As needed rapid-acting β2-agonist As needed rapid-acting β2-agonist

Low-dose ICS pluslong-acting β2-agonist

Select one

Leukotrienemodifier**

Select one

Medium-orhigh-dose ICS

Medium-or high-doseICS plus long-acting

β2-agonist

Low-dose ICS plusleukotriene modifier

Low-dose ICS plussustained release

theophylline

To Step 3 treatment,select one or more

To Step 4 treatment,add either

Asthma education. Environmental control.(If step-up treatment is being considered for poor symptom control, first check inhaler technique, check adherence, and confirm symptoms are due to asthma.)

Low-dose inhaledICS*

Oral glucocorticosteroid(lowest dose)

Anti-IgEtreatment

Leukotrienemodifier

Sustained releasetheophylline

Controlled Maintain and find lowest controlling step

Partly controlled Consider stepping up to gain control

Uncontrolled Step up until controlled

Exacerbation Treat as exacerbation

Treatment ActionLevel of Control

Red

uce

Reduce Increase

Incr

ease


*** = Recommended treatment (shaded boxes) based on group mean data. Individual patient needs, preferences, and circumstances (including costs) should be considered.

Figure 4.3-2.

For management of asthma in children 5 years and younger, refer to the Global Strategy for the Diagnosis and Management of Asthma in Children 5 Years and Younger, available at http://www.ginasthma.org.

Alternative reliever treatments include inhaled anticholinergics, short-acting oral β2-agonists, some long-acting β2-agonists, and short-acting theophylline.Regular dosing with short and long-acting β2-agonists is not advised unless accompanied by regular use of an inhaled glucocorticorsteriod.

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• Asthma monitoring is a collaboration between the patient and the medical team

• Successful monitoring helps to achieve good control and reduces hospitalisation

• Monitoring is only useful if the results are acted upon• Asthma monitoring should be incorporated with a pre-specified

written asthma management plan• For most people with asthma, self-monitoring through recognition

of key symptoms is sufficient• People with more severe asthma, or those who have difficulty

recognising changes in severity, may benefit from more detailed monitoring

• Monitoring may also be helpful in specific situations such as assessing response to a trial of treatment or diagnosis of occupational airways disease

• Emerging technologies (electronic monitors, telemonitoring) and biomarkers have great potential but more research is needed

The variable nature of asthma means that active monitoring is re-quired to optimise treatment. The aim of monitoring is to assess dis-ease control and allow proactive changes in management. When successful, this approach leads to reduced symptoms, improved qual-ity of life and fewer serious events such as hospitalisation. Proactive monitoring also permits prompt reduction in medication, where ap-propriate, minimising side-effects.

There are many forms of moni-toring, both community and clinic based (Figure 1), but to succeed, all rely on a collaboration between the patient and medical team. Monitor-ing is not a therapeutic end in itself, to be useful results must be acted upon. Monitoring options include relying on symptoms, reliever use, measures of airflow obstruction and biomarkers (Table 1).

SYMPTOMS AND MEDICATION USEThe simplest and most commonly used form of monitoring is based on recognition of key symptoms. For the majority of people with asthma, their symptoms and need for reliever inhalers are accurate guides to disease activity. When patients are provided with an agreed written asthma manage-

ment plan (Figure 2), they are able to respond to changes in symptoms with appropriate changes in medi-cation and to seek help promptly where appropriate.

Patients with moderate to severe disease, and those who are poor perceivers of changes in asthma control, may benefit from the addi-tion of peak flow measurements at home.

In the clinic setting, patient’s con-troller adherence, exacerbation

history and asthma control should be reviewed. Short questionnaires such as the Asthma Control Test (ACT) may improve consistency of assessment over time.

MEASURES OF AIRFLOW OBSTRUCTION / AIRWAY RESPONSIVENESSThe degree of airway narrowing in asthma varies over time and is usually assessed with tests of lung function such as spirometry or peak flow monitoring. Spirometry

ASTHMA MONITORING25

Ke y m e ssag e s

James Fingleton Richard Beasley Medical Research Institute

Wellington, New Zealand

Asthma monitoring

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requires more expensive equip-ment and staff training and is main-ly used in primary care or hospital settings, whereas peak flow meters can be used anywhere, including the home.

All airflow measurements show some natural variation over time but large variations in peak flow suggest poorly controlled asthma. Patients with asthma and signifi-cant variability in their peak flow show an improvement in peak flow and a reduction in variability once treated with inhaled corticoster-oids (Figure 3).

Peak flow monitoring is simple, relatively inexpensive, and widely available, and therefore features prominently in current asthma guidelines. However, values are

effort dependent, a single reading provides limited information, and diaries are reviewed only in retro-spect. There is accordingly interest in methods of electronic PEF mon-itoring which may provide a more accurate and contemporaneous assessment.

EMERGING TECHNOLOGIES / ELECTRONIC MONITORINGThe simplest forms of electronic monitoring are electronic diaries, which prompt the patient to take a peak flow reading and then enter it into the diary. These may improve adherence to treatment and moni-toring and are widely used in clini-cal trials, however as yet they have not been shown to improve patient outcomes.

Telemonitoring, where informa-tion on symptoms and peak flow is collected regularly and reviewed remotely, has the potential to im-prove outcomes if it aids recog-nition of worsening control and treatment is changed appropriate-ly. Trials have suggested that pa-tients like telemonitoring systems, but have not consistently shown an improvement in control or re-duction in exacerbations. Potential alternatives could include inhalers with built-in monitoring devices which recognise increasing reliever use and prompt the patient to seek early medical review, as patient symptoms, peak flow readings and rescue inhaler use increase up to 10 days before an exacerbation is recognised and treated (Figure 4).

Figure 1 Different forms of asthma monitoring.

Figure 2 Example of an Asthma Management Plan. (Asthma New Zealand)

TABLE 1

Patient education for self-management of asthma during pregnancy

Causal agents Selected jobs or industries

Symptoms and medication use

• Symptoms and limitation of activity

• Reliever use

• Controller adherence

• Symptom questionnaires, e.g. ACT

• Electronic symptom monitoring

Exacerbation his-tory in past year

• Number of exacerbations

• Number of courses of oral steroids

Measures of Air-flow obstruction / responsiveness

• Peak Flow Meter

• Spirometry

• Airways responsiveness

Biomarkers / Inflammometry

• Induced sputum

• Exhaled nitric oxide

• Blood biomarkers

First line techniques which can be used in any setting, including the homeTechniques suitable for primary and secondary care

Techniques best suited to specialist careEmerging techniques not yet proven to be clinically beneficial for long term monitoring

Asthma monitoring

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Asthma monitoring

Figure 3 Example of a peak flow diary showing improved peak flow and reduced variability in response to starting a steroid inhaler. (Reprinted from Allergy, 3rd

edition, Platts-Mills T AE, Adachi M, Pauwels RA, et al, Asthma, 26, Copyright 2006, with permission from Elsevier.)

Figure 4 Change in peak flow, symptoms and rescue inhaler use around an exacerbation. Day 0 is the day an exacerbation was diagnosed. (Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic

Society. Tattersfield AE, Postma DS, Barnes PJ, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group.

Am J Respir Crit Care Med 1999;160:594-599. Official journal of the American Thoracic Society.)

BIOMARKERS / INFLAMMOMETRYAs some people with asthma are recognised to be “poor perceivers” of worsening control, and meas-ures of airflow obstruction are effort dependent, there is consid-erable interest in identifying bio-markers that can effectively iden-tify patients at high risk of future exacerbation or who may benefit from a change in treatment. As yet there are no biomarkers which are suitable for widespread use in guiding treatment, but research is ongoing into different techniques including induced sputum exam-ination and exhaled nitric oxide measurement, as well as possible blood biomarkers which may guide doctors about the type and severi-ty of inflammation in the lung and the type of treatment a patient may respond to. As our knowledge of biomarkers improves, the pros-pect of true personalised medicine, where proactive monitoring leads to the right medication for an indi-vidual at the right time, should be-come a reality.

KEY REFERENCES1. Gibson PG, Powell H, Coughlan

J, Wilson AJ, Abramson M, Hay-wood P, et al. Self-management education and regular practition-er review for adults with asth-ma. Cochrane Database Syst Rev 2003;(1):CD001117.

2. Ryan D, Price D, Musgrave SD, Malhotra S, Lee AJ, Ayansina D, et al. Clinical and cost effectiveness of mobile phone supported self monitoring of asthma: multicentre randomised controlled trial. BMJ 2012;344:e1756.

3. Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O’Byrne PM, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Am J Respir Crit Care Med 1999;160:594-599.

%100

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0

-15 -10 -5 0 5 10 15DAY

PEF Morn.PEF Even.

Symptoms NightSymptoms Day

Rescue NightRescue Day

Section B

DISEASES ASSOCIATED

WITH ASTHMA

* Atopy and asthma* Upper airway diseases and asthma* Asthma and obesity, the twin epidemics* Aspirin exacerbated respiratory disease* Gastro-esophageal reflux disease and asthma* Cardiovascular diseases and asthma* Food allergy and asthma* Skin and lung: atopic dermatitis, urticaria and asthma

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• Atopy is a risk factor for asthma, especially in children• Asthma and rhinitis commonly co-exist• The epidemiology suggests the causes of asthma and allergic

sensitisation are probably different• Treating rhinitis may improve asthma symptoms, especially cough• Allergic triggers are important in asthma, but allergen avoidance

has been disappointing as a means of controlling asthma

The association between atopy and asthma has long been recognised: asthma and other allergic con-ditions often run in families, and many patients are aware of allergic triggers for their asthma. Atopic eczema is often the first sign that a child has the atopic phenotype, and may go on to develop rhinitis and asthma as they grow up. About 75% of adults with asthma have allergic rhinitis and 50% of people with allergic rhinitis have asthma, although this is not always clinical-ly recognised. Genetic studies have identified several candidate genes, some of which are linked to regu-lation of Th2-pattern cytokines or epidermal barrier function. How-ever, the variability of the clinical phenotype suggests that the de-velopment of clinically apparent atopic disease involves complex gene-environment interactions (Figure 1).

Both asthma and childhood wheez-ing illness have increased steadily over the past 50 years, in parallel with increasing rates of other atop-ic conditions such as rhinitis, ecze-ma and food allergy. Studies of the natural history of asthma showed that wheeze in the first 3 years of life often resolves, whereas persis-tent asthma often starts after the

age of three years. Wheezing up to the age of 18 months is unrelated to the risk of developing atopy by age seven years, but being atopic is linked to wheeze that persists into later childhood. In other words, early wheeze is likely to be driven by infection but atopy is a key risk factor for persistent asthma.

How allergy and other inflamma-tory processes interact to produce the acute and chronic features of asthma should be envisaged in a complex framework (Figure 2). Having an atopic parent increas-es the risk of developing asthma, but this risk interacts with risks conferred by maternal smoking: children with one atopic parent are seven times more likely to de-velop allergic sensitisation and 5.7 times more likely to wheeze if their

mother smokes during or after pregnancy, as compared to having a non-smoking mother.

However, the general increase in rates of asthma cannot be blamed solely on allergic sensitisation. We have done many things to improve our living conditions which have made our houses more friendly to house dust mites, and the allergen concentrations in European houses have increased dramatically over the past 50 years, but the overall rate of house dust mites (HDM) sensitisation has not changed anything like as much as the rate of asthma.

Asthma and rhinitis commonly co-exist. The nasal and airway mu-cosa are similar and show similar patterns of cellular inflammation after exposure to allergens. Rhinitis

Anthony J. Frew Royal Sussex County Hospital

Brighton, UK

ATOPY AND ASTHMA1

Ke y m e ssag e s

Atopy and asthma

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Atopy and asthma

is present in about 75% of people with asthma; conversely asthma is present in about 50% of people with allergic rhinitis. Treating rhi-nitis improves asthma control. This may be through damping down the systemic effects of eosinophilic in-flammation in the nose, or it may be simply due to reduction in nasal secretions dripping down onto the larynx. Either way it is important to recognise rhinitis in patients with asthma and treat it appropriately.

The link between atopic eczema and asthma is less clear-cut. Being atopic is a risk factor for develop-ing asthma, so eczema and asthma are linked, but there is no evidence that treating eczema alters the natural history of asthma.

KEY REFERENCES 1. Sly PD, Boner AL, Björksten B,

Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persis-tent asthma in children. Lancet

2008;372:1100-1106.

2. Neuman Å, Hohmann C, Orsini N, Pershagen G, Eller E, Kjaer HF, et al. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med 2012;186:1037-1043.

3. Rochat MK, Illi S, Ege MJ, Lau S, Keil T, Wahn U, et al. Allergic rhinitis as a predictor for wheezing onset in school-aged children. J Allergy Clin Immunol 2010;126:1170-1175.e2.

Figure 1 Risk factors for the development of atopy and asthma.

Figure 2 Conceptual framework showing how allergy and other

inflammatory processes interact to produce the acute and chronic features of asthma. URTI - upper

respiratory tract infection.Bronchial Irritability Chronic Changes

Wheeze & Bronchospasm

Fixed Airway Obstruction

Allergy ChemicalsViruses

Airway Inflammation

Susceptible Airway

AllergyURTIDust

Fumesetc}

Genetic predisposition(Chr 5, 6, 11, 12, 14 etc)

Naiveimmunesystem

Germ-free environmentNo siblingsAntibioticsVaccination

Low lactobacillusIndustrialisation

Living on farmsEarly infectionsOlder siblings

Day care exposureHelminth infestationHepatitis A infection

No Allergyor Asthma

Protectiveresponse

Th2response

Allergy& Asthma

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with chronic upper or lower airway symptoms• Both allergic and non-allergic rhinitis represent risk factors for

the development of asthma• Chronic rhinosinusitis with/without nasal polyps often occur

together with asthma• The interaction between chronic upper and lower airway

inflammation has primarily been studied in allergic individuals• The presence of asthma is a negative predictor of outcome after

endoscopic sinus surgery for chronic rhinosinusitis with/without nasal polyps

Due to its’ strategic position at the entry of the airways, the nose plays a crucial role in airway homeosta-sis. By warming up, humidifying and filtering the inspired air, the nose is essential in the protection and homeostasis of the lower airways. The nose and bronchi are linked an-atomically, and both are lined with a pseudo-stratified respiratory epi-thelium and equipped with an arse-nal of innate and acquired immune defense mechanisms. It is not hard to imagine that nasal pathology bypassing the function of the nose may become a trigger for lower airway pathology in susceptible individuals. It is however evident that the nasobronchial interaction is not restricted to bronchial reper-cussions of hampered nasal func-tion. The nose and bronchi seem to communicate via mechanisms such as neural reflexes and systemic pathways (Figure 1). Bronchocon-striction following exposure of the nose to cold air suggests that neu-ral reflexes connect nose and lung. The neural interaction linking the release of inflammatory mediators in the bronchi following a nasal in-flammatory stimulus has recently been shown by bronchial release of neural mediators after selective nasal allergen provocation. The systemic nature of the interaction

between nose and bronchi involves the blood stream and bone mar-row (Figure 2). In addition, genetic factors may as well play a role in the manifestation of nasal and/or bronchial disease.

In the context of global airway dis-ease, it is important to recognize the epidemiologic and pathophysi-ologic link between upper and low-er airways (Figure 3). Both allergic as well as non-allergic rhinitis are major risk factors for the devel-opment of asthma. Therefore, it is not a surprise to find that most patients with asthma present with symptomatic or even asympto-matic upper airway inflammation. Beside rhinitis, asthma patients

are more susceptible to develop recurrent acute or chronic rhinosi-nusitis (CRS). Interestingly, most patients with CRS who do not re-port to have asthma show bron-chial hyperresponsiveness when given a metacholine challenge test. Histopathologic and immunologic features of CRS and asthma large-ly overlap. Recently, the nasal ap-plication of Staphylococcus aureus enterotoxin B has been shown to aggravate the allergen-induced bronchial eosinophilia in a mouse model. Medical treatment for CRS has been shown to be beneficial for asthma, as well as endoscopic sinus surgery (ESS). Interestingly, the presence of lower airway disease may have a negative impact on the

UPPER AIRWAY DISEASES AND ASTHMA2

Ke y m e ssag e s

Peter W. Hellings University Hospitals Leuven

Belgium

Upper airway diseases and asthma

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IL-3IL-5IL-9GM-CSFEotaxinSDF-1

Allergens

Infection

HemopoieticProgenitor

homing

Figure 1 Mechanisms explaining the naso-bronchial interaction. (Modified from Bergeron C, Hamid Q. Relationship between Asthma and Rhinitis: Epidemiologic, Pathophysiologic, and Therapeutic Aspects. Allergy Asthma Clin Immunol 2005;1:81-87.

Reprinted with permission under the Creative Commons Attribution License or equivalent.)

Figure 2 Systemic inflammation in asthma and rhinitis. (Reproduced with permission from the American College of Chest Physicians from Denburg JA, Keith PK.

Eosinophil progenitors in airway diseases: clinical implications. Chest 2008;134:1037-1043.)


outcome after ESS. Poor outcomes after ESS have also been reported in patients with aspirin-intolerant asthma. Aspirin-intolerant asth-ma is a distinct clinical syndrome characterized by the triad aspi-rin sensitivity, asthma and nasal polyps (NP) and has an estimated prevalence of one percent in the general population and ten percent among asthmatics. Increased na-sal colonization by Staphylococcus aureus and presence of specific IgE directed against Staphylococcus au-reus enterotoxins were found in NP patients. Interestingly, rates of col-onization and IgE presence in NP tissue were increased in subjects with NP and co-morbid asthma or aspirin sensitivity. By their supe-rantigenic activity, enterotoxins may activate inflammatory cells in an antigen-unspecific way.

No well-conducted trials on the effects of medical therapy for NP on asthma have been performed so far. After ESS for NP in patients with concomitant asthma, a signifi-cant improvement in lung function and a reduction of systemic steroid use was noted, whereas this was

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Figure 3 Global Airway Disease. (Reproduced from Hellings PW, Prokopakis EP. Global airway disease beyond allergy. Curr Allergy Asthma Rep. 2010;10:143-149 with kind permission of Springer Science + Business Media.)

not the case in aspirin-intolerant asthma patients. Data on effects of surgery for NP on asthma mostly point towards a beneficial effects of surgery on different parameters of asthma.

The upper airways of chronic ob-structive lung disease (COPD) patients remain less studied than in asthma in spite of the fact that a majority of COPD patients pre-senting at an academic unit of respiratory disease do experience sinonasal symptoms (Figure 1). Several pro-inflammatory media-tors have been found in nasal lav-ages of COPD patients and nasal symptoms corresponded with the overall impairment of the quality of life. A high number of patients with bronchiectasis have shown to pres-ent with rhinosinusitis symptoms, radiologic abnormalities on CT scans and have a reduced smell ca-pacity. The impact of upper airway treatment in patients with COPD and bronchiectasis still needs to be

properly investigated.

KEY REFERENCES1. Hens G, Hellings PW. The nose:

gatekeeper and trigger of bronchi-al disease. Rhinology 2006;44:179-187.

2. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and na-sal polyps 2012. A summary for otorhinolaryngologists. Rhinology. 2012;50:1-12.

3. Hens G, Raap U, Vanoirbeek J, Meyts I, Callebaut I, Verbinnen B, et al. Selective nasal allergen provocation induces substance P-mediated bronchial hyperres-ponsiveness. Am J Respir Cell Mol Biol 2011;44:517-523.

4. Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet 2011;378:2112-2122.

5. Ponikau JU, Sherris DA, Kephart GM, Kern EB, Gaffey TA, Tarara JE, et al. Features of airway re-modeling and eosinophilic inflam-mation in chronic rhinosinusitis:

is the histopathology similar to asthma? J Allergy Clin Immunol 2003;112:877-882.

6. Hellings PW, Hens G, Meyts I, Bul-lens D, Vanoirbeek J, Gevaert P, et al. Aggravation of bronchial eosin-ophilia in mice by nasal and bron-chial exposure to Staphylococcus aureus enterotoxin B. Clin Exp Al-lergy 2006;36:1063-1071.

7. Hens G, Vanaudenaerde BM, Bul-lens DM, Piessens M, Decramer M, Dupont LJ, et al. Sinonasal pa-thology in nonallergic asthma and COPD: ‘united airway disease’ be-yond the scope of allergy. Allergy 2008;63:261-267.

8. Hurst JR, Wilkinson TM, Don-aldson GC, Wedzicha JA. Upper airway symptoms and quality of life in chronic obstructive pulmo-nary disease (COPD). Respir Med 2004;98:767-770.

9. Guilemany JM, Angrill J, Alobid I, Centellas S, Pujols L, Bartra J, et al. United airways again: high preva-lence of rhinosinusitis and nasal polyps in bronchiectasis. Allergy 2009;64:790-797.

ASTHMACOPD

BRONCHIECTASIS

NASALPOLYPS

RHINITISInfectiousAllergic

Noninfectious,nonallergic

RHINOSINUSITISAcute

Chronic

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• Asthma and obesity are related chronic disease epidemics• Obesity modifies asthma, resulting in the obese-asthma

phenotype• The physiological changes in obese asthma include reduced

expiratory reserve volume and airway closure during tidal breathing

• Adipose tissue is inflamed leading to proinflammatory cytokine and adipokine production

• Airway inflammation is altered to a non-eosinophilic pattern• These changes may contribute to treatment resistance in obese

asthma• Management of asthma in obese patients requires intervention at

both the individual and societal levels• Effective public health interventions are urgently required

Asthma and obesity are linked global chronic disease epidemics. The prevalence of both diseases is high and shows considerable geo-graphic variation (Figure 1). Obesi-ty can potentiate the development and clinical severity of asthma. Like all chronic disease epidemics, asth-ma and obesity often begin in child-hood and several different chronic different diseases may occur in the same person. The approach to pre-vention and treatment of the asth-ma and obesity epidemics needs to be long-term and systematic.

Obesity modifies the clinical ex-pression of asthma, resulting in the obese-asthma phenotype (Table 1). Deposition of adipose tissue in the thoracic and abdominal re-gions leads to lung restriction and physiological changes such as re-duced expiratory reserve volume (the earliest change in static lung volumes) and airway closure dur-ing tidal breathing. This results in loss of the ‘physiological breathing space’, the gap between tidal and maximal expiratory airflow (Figure 2). In obesity, asthma symptoms are worse, and response to asthma treatment is impaired. Adipose tis-sue is inflamed with an infiltration of macrophages and mast cells, leading to proinflammatory cy-

ASTHMA AND OBESITY, THE TWIN EPIDEMICS3

Ke y m e ssag e s

Peter G. Gibson University of Newcastle

NSW, Australia

Asthma and obesity, the twin epidemics

tokine and adipokine production (Figure 3). This results in chronic low-grade systemic inflammation with elevated C-reactive protein levels and increased cardiovas-cular risk. In obese asthma, the changes in adipokines such as lep-tin are enhanced (Figure 4), and the pattern of airway inflammation is altered to a non-eosinophilic pat-tern, with elevated neutrophils in women with obese asthma. These changes may contribute to treat-ment resistance in obese asthma.

Obesity results from an imbalance between caloric intake and energy

expenditure. This includes eating excessive amounts of food that is high in saturated fat and reduc-ing physical activity levels. Both of these changes are increasingly prevalent in modern urbanized so-cieties, and identify the important social and political dimensions to obesity and its management. Con-sumption of a meal that is high in saturated fat leads to systemic in-flammation with elevated C-reac-tive protein in obese asthma. There are, in addition, changes to the asthmatic airway indicating acti-vation of innate immune responses with elevated gene expression for

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b Prevalence of overweight (%)< 2020-39.9

40-59.9≥ 60

Data not availableNot applicable

*BMI ≥ 25 kg/m2

aProportion of population (%)

≥10.1

7.6-10.0

5.1-7.5

2.5-5.0

0-2.5

No standardised data available

Toll-like receptor 4 and elevated neutrophils, and activation of the pathways as depicted in Figure 3. The associated functional conse-quences include reduced broncho-dilator responsiveness.

Management of obese asthma re-quires intervention at both the in-dividual and societal levels. Weight loss leads to improved asthma and can even lead to resolution of asth-ma in some individuals. Weight loss can be achieved by caloric restriction and bariatic surgery. Increasing physical activity during weight loss can minimize the loss of lean body mass (skeletal mus-cle). The goals of weight reduction need to be clearly defined for in-dividuals, and can be to reverse obesity or to improve the asthma. Large amounts of weight loss are required to reverse obesity, how-ever only a modest weight loss of 10% body weight is sufficient to improve the medical complications of obesity, including asthma.

Effective public health interven-tions are urgently required at a so-cietal level to manage the obesity epidemic, and its adverse impact on asthma.

KEY REFERENCES1. Bousquet J, Khaltaev N, editors.

Global surveillance, prevention and control of chronic respira-tory diseases : a comprehensive approach. Geneva: WHO Press, 2007.

2. Lugogo NL, Kraft M. Dixon AE. Does obesity produce a distinct asthma phenotype? J Appl Physiol 2010;108:729-734.

3. Gibson PG. Obesity and Asthma. Ann Am Thorac Soc 2013;in press.

4. Lugogo N, Bappanad, Kraft M. Obesity, metabolic dysregu-lation, and oxidative stress in asthma. Biochem Biophys Acta 2011;1810:1120-1126.

5. Berthon BS, Macdonald-Wicks LK,

Figure 1 World map of the prevalence of asthma (panel a) and obesity (panel b). (Panel a reproduced from Masoli M, Fabian D, Holt S, et al. The global burden of

asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59:469-8 with permission from Wiley-Blackwell. Panel b reproduced from World

Health Organisation, Global Health Observatory.)

TABLE 1

Characteristics of the obese asthma phenotype *

Worse asthma control

Decreased response to controller medication

Presence of comorbidities related to obesity

Presence of metabolic/immune derangements related to obesity

* Reproduced from Lugogo NL, Kraft M, Dixon AE, Does obesity produce a distinct asth-ma phenotype? J Appl Physiol 2010;108:729-734 with permission of The American Physiological Society.

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Figure 3 Inflammatory pathways in obesity leading to altered systemic and pulmonary inflammatory responses in asthma. (Reprinted from Biochem Biophys Acta, 1810/11, Lugogo N, Bappanad, Kraft M. Obesity, metabolic dysregulation, and oxidative

stress in asthma, 1120-1126, Copyright 2011, with permission from Elsevier.)

Figure 4 Elevated leptin in obesity and asthma, and effects of gender.

(Reproduced from Berthon BS, Macdonald-Wicks LK, Gibson PG, et al. An investigation

of the association between dietary intake, disease severity and airway inflammation in asthma. Respirology 2013;18:447-454 with

permission from John Wiley and Sons, Inc.)


Figure 2 Effects of obesity (solid lines) on airway physiology. Compared to normal (dotted lines), obesity leads to reduced static lung volumes (bars) and airflow limitation during tidal breathing in the expiratory flow volume curve, resulting in

loss of the ‘breathing space’, the gap between tidal flow and maximal expiratory flow. TLC - total lung volume; FRC - forced

residual capacity; RV - residual volume (Reproduced from Farah CS, Salome CM. Asthma and obesity: a known association but unknown mechanism. Respirology 2012;17:412-421 with

permission from John Wiley and Sons, Inc.)

Volume (L)

Obesity

PredictedRVFRCTLC

Flow

(L/m

in)

Gibson PG, Wood LG. An investi-gation of the association between dietary intake, disease severity and airway inflammation in asth-

ma. Respirology 2013;18:447-454.

6. Wood LG, Garg ML, Gibson PG. A high-fat challenge increases airway inflammation and im-

pairs bronchodilator recovery in asthma. J Allergy Clin Immunol 2011;127:1133-1140.

10000

9000

8000

7000

6000

5000

4000

3000

2000

1000

Healthy Control Asthma

Lept

in (p

g/m

l)

Female

Male

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ated

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ma • Aspirin Exacerbated Respiratory Disease (AERD) is a distinct

phenotype of asthma with coexisting chronic rhinosinusitis, nasal polyps and hypersensitivity to aspirin and to other non-steroidal anti-inflammatory drugs

• AERD is characterized by an increased risk for uncontrolled upper and lower airway disease

• Patients with AERD require comprehensive and multidisciplinary diagnostic approach

• Management of asthma and rhinosinusitis in a patient with AERD is similar to other forms of asthma and rhinosinusitis

• Aspirin desensitization may be an effective treatment option for some AERD patients

DEFINITION AND CLINICAL CHARACTERISTICS OF AERDAspirin Exacerbated Respiratory Disease (AERD) is a distinct clini-cal syndrome observed in 5-10% of patients with asthma and char-acterized by history of acute dysp-nea usually accompanied by nasal symptoms (rhinorrhoea and/or nasal congestion) within two hours after ingestion of acetylsalisilic acid (ASA) (Figure 1). These patients suffer from chronic, usually severe rhinosinusitis with recurrent nasal polyps and do not tolerate other non-steroidal anti-inflammatory drugs (NSAIDs), which are strong cyclooxygenase-1 (COX-1) inhibi-tors. The syndrome has been previ-ously called “Aspirin-triad” or “As-pirin-Sensitive Asthma”. Patients with AERD are quite heterogene-ous with respect to asthma sever-ity, presence of atopic sensitization (up to 70% may be atopic) and gen-eral responsiveness to treatment. However, on average AERD is as-sociated with increased risk for severe asthma, frequent exacerba-tions and sudden death.

PATHOGENESIS OF AERD AND HYPERSENSITIVITY TO NSAIDSThe mechanism of hypersensitivity to ASA and NSAIDs in asthmatic patients is not immunological, but

is related to inhibition of COX-1, an enzyme that converts arachi-donic acid into prostaglandins, thromboxanes and prostacyclin. According to the “ prostaglandin/cyclooxygenase theory” proposed by Andrew Szczeklik inhibition of COX-1 by ASA or other NSAID, by depriving the system from prostaglandin E2 (PGE2) triggers activation of inflammatory cells (mast cells, eosinophils and plate-lets) with subsequent release of inflammatory mediators, including cysteinyl leukotrienes (Figure 2). Baseline abnormalities of arachi-donic acid metabolism (e.g. PGE2 deficiency and overproduction of leukotrienes), persistent viral in-

fections, Staphylococcus aureus en-terotoxins and underlying genetic predisposition may have important role in the pathogenesis of chronic eosinophilic inflammation typically present in the upper and lower air-way mucosa of AERD patients.

DIAGNOSIS OF NSAID HYPERSENSITIVITYIn the majority of patients the di-agnosis of ASA/NSAID hypersen-sitivity can be based on a history of respiratory symptoms induced by the ingestion of aspirin or oth-er NSAIDs. Confirmation by con-trolled aspirin challenge may be necessary in some patients. Oral aspirin provocation (Figure 3) is

ASPIRIN ExACERBATED RESPIRATORY DISEASE4

Ke y m e ssag e s

Marek L. Kowalski Medical University of Łódź

Poland

Sevim Bavbek Ankara University

Turkey

Aspirin exacerbated respiratory disease

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Figure 1 Clinical characteristics of Aspirin Exacerbated Respiratory Disease.

Figure 2 Pathomechanism of aspirin induced hypersensitivity reactions in AERD patients. (Reproduced and modified from Kowalski ML. Diagnosis of aspirin

sensitivity in aspirin exacerbated respiratory disease. In: Pawankar R, Holgate ST, Rosenwasser LJ, editors. Allergy frontiers: diagnosis and health economics. New York:

Springer, 2009; 349-372, with kind permission of Springer Science + Business Media.)

the gold standard for the diagnosis, but bronchial or nasal provocation with lysine-ASA may be valuable alternative diagnostic tools. Sever-

al in vitro cell activation tests have been evaluated, but none of them can be recommended for routine diagnosis.

Hypersensitivityto ASA

Chronic rhinosinusitis

with nasal polypsAsthma

• Cross- reactivity with COX-1 inhibitors

• General tolerance of COX-2 inhibitors

• Hyperplastic pansinusitis

• Recurrent nasal polyps• Hyposmia

• More severe than average

• More difficult to control• Increased death risk

Aspirin triad

ASA Arachidonic acid

Cell membrane phospholipids

15-LOX

15-HPETE

15-HETE

EoxinsLipoxins

COX-1

PLA

LTA4

LTC4

LTD4

LTE4

LTC4s

5-LOX

AsthmaRhinorrheaCongestion

UrticariaAngioedema

PGG2PGH2

PGE22

Eos Mast cell

Platelets

PGE2

EP-R

EP-R

COX-2

MANAGEMENT OF AERDCareful avoidance of ASA and oth-er NSAIDs, which are strong COX-1 inhibitors, is necessary to prevent severe asthma attacks. As alter-native to NSAIDs acetaminophen or preferential/selective COX-2 inhibitors, are recommended (Ta-ble 1). Management of asthma and rhinosinusitis in AERD is similar to other forms of asthma and rhinosi-nusitis and international treatment guidelines should be followed. Inhaled glucocorticosteroids in appropriate doses, often in combi-nation with long acting beta-2 ag-onists are effective in controlling asthmatic inflammation and symp-toms, but in some patients chronic treatment with oral prednisone may be necessary.

Addition of a leukotriene receptor antagonist such as montelukast to standard anti-inflammatory ther-apy may be effective in relieving symptoms and improving respira-tory function in some patients with AERD, but the degree of improve-ment is similar to ASA tolerant asthmatics. Topical nasal steroids are preferred for controlling symp-toms of rhinosinusitis and may slow down recurrence of nasal pol-yps. Surgical procedures (polypec-tomy, functional endoscopic sinus surgery or ethmoidectomy) are usually needed at certain stage of the disease.

The special approach for these pa-tients is ASA desensitization. The alleviation of chronic upper and lower airway symptoms, reduction in hospitalization and emergency room visits, and decreased need for nasal/sinus surgery is observed in desensitized patients. Howev-er, only a fraction of patients with AERD will benefit from aspirin de-sensitization and at present it is not possible to predict the responders.

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Figure 3 Oral aspirin challenge test report in a patient with AERD. The significant drop in FEV1

(>20% baseline) supports the diagnosis of aspirin

intolerance.


TABLE 1

NSAIDs tolerance in patients with AERD *

Group A: NSAIDs cross-reacting in the majority of hypersensitive patients (60–100%)

Diclofenac Etololac

Fenoprofen Flurbiprofen

Ibuprofen Indomethacin

Ketoprofen Ketorolac

Meclofenamate Mefenamic acid

Nabumetone Naproxen

Piroxicam Sulindac

Group B: NSAIDs cross-reacting in a minority of hypersensitive patients (2–10%)

Rhinitis/asthma type

acetaminophen (doses below 1000 mg)

meloxicam

nimesulide

Urticaria/angioedema type

acetaminophen

meloxicam

nimesulide

selective COX-2 inhibitors (celecoxib, rofecoxib)

Group C: NSAIDs well tolerated by all hypersensitive patients **

Rhinitis/asthma type

selective cyclooxygenase inhibitors (celecoxib, parvocoxib)

trisalicylate, salsalate

Urticaria/angioedema type

new selective COX-2 inhibitors (etoricoxib, pavocoxib)

* Reproduced from Kowalski ML, Makowska JS, Blanca M, et al. Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and manage-ment: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy 2011;66:818-829. ** Single cases of hypersensitivity have been reported

20

10

0

-10

-20

-30

-40

08:2

5

08:5

9

09:3

1

10:3

4

11:3

0

14:4

4

27 m

g

44 m

g

117

mg

Nebulized salbutamol (1.5 mg)

% d

ecre

ase

in F

EV

1

Time line Before ASA

After 117 mg ASA

12

8

4

0

4

8

2 4 8Volume

(L)

Flow(L/s)

KEY REFERENCES1. Stevenson DD, Szczeklik A. Clini-

cal and pathologic perspectives on aspirin sensitivity and asthma. J Al-lergy Clin Immunol 2006;118:773-786.

2. Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, et al. Hypersensitivity to nonsteroidal anti-inflamma-tory drugs (NSAIDs) - classifica-tion, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy 2011;66:818-829.

3. Lee RU, Stevenson DD. Aspi-rin-exacerbated respiratory dis-ease: evaluation and manage-ment. Allergy Asthma Immunol Res 2011;3:3-10.

4. Chang JE, White A, Simon RA, Stevenson DD. Aspirin-exacer-bated respiratory disease: burden of disease. Allergy Asthma Proc 2012;33:117-121.

5. Shrestha Palikhe N, Kim SH, Jin HJ, Hwang EK, Nam YH, Park HS. Genetic mechanisms in aspirin-ex-acerbated respiratory disease. J Allergy (Cairo) 2012;2012:794890.

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• Gastro-esophageal reflux disease (GERD) is an increase of retrograde movement of gastric content into the esophagus

• Laryngopharyngeal reflux is reflux which reaches the larynx• Ten to 20% of the general adult population in western countries

and 5% of subjects in the Asia Pacific region suffer from GERD• Asthma and/or upper airway complaints or problems are

associated with GERD• Double-blind controlled studies demonstrate that treatment

of asymptomatic GERD in adults and children does not improve asthma

• Just as GERD may aggravate asthma, so too, could asthma or asthma therapy aggravate GERD

• Diagnosis of GERD in both adults and children is primarily suspected and made by a detailed history

• Treatment includes lifestyle changes and where necessary H2 blockers, proton pump inhibitors and prokinetics

Gastroesophageal reflux disease (GERD) is an increase of retrograde movement of gastric content into the esophagus. Laryngopharyngeal reflux is reflux which reaches the larynx. GERD is present when the frequency and duration of acid re-flux exceeds defined parameters, as quantified by a pH probe placed in the esophagus. Regardless of its more formal definition, it is a dis-ease in and of itself, often associat-ed with esophageal complications such as esophageal erosion and stricture and Barrett’s esophagus, the latter of which can lead to ad-enocarcinoma of the esophagus. Factors which contribute to or cause GERD are illustrated in Fig-ure 1.

Ten to 20% of the general adult population in western countries and 5% in the Asia Pacific region suffer from symptoms of GERD. The presence of GERD in some pediatric studies is between 2-8%. Typical symptoms particularly in adults, include esophageal burning and discomfort (heartburn) as well as regurgitation of gastric content into the posterior pharynx (wa-ter brash) (Table 1). Other symp-toms include belching, indigestion, nausea, vomiting, odynophagia, dysphagia, and halitosis. Throat

tightness, throat clearing, cough, chest tightness, postnasal drip, and hoarseness are all potential symp-toms of GERD, particularly with la-ryngeal pharyngeal reflux. Cough, associated with laryngopharyn-geal GERD, is usually described as originating in the laryngopharynx, whereas cough associated with asthma usually originates in the chest; however, this distinction is subjective as can be differentiat-ing the symptoms of cough from throat clearing. The same symp-toms can occur in children, how-

ever, recurrent regurgitation, with or without vomiting, weight loss or poor weight gain, irritability, and behavioral problems may occur.

Asthma and/or upper airway com-plaints or problems are associated with GERD. Epidemiologic studies demonstrate a variable prevalence in subjects with asthma of between 12 to 85%. The variability is largely dependent on the method used to define GERD. Conversely, asthma also appears to be more common in individuals with GERD. Two hy-

GASTRO-ESOPHAGEAL REFLUx DISEASE AND ASTHMA5

Ke y m e ssag e s

Richard F. Lockey University of South Florida

USA

Gastro-esophageal reflux disease and asthma

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trolled studies in both adults and children with asthma indicates that treating GERD does not increase asthma control but does decrease the use of albuterol; it benefited a subset of affected patients.

Just as GERD may aggravate asthma, so too, could asthma or asthma therapy aggravate GERD or GERD-associated symptoms. Beta agonists and theophylline re-duce esophageal sphincter tone, systemic glucocorticosteroids increase gastric acid production, and inhaled corticosteroids induce cough and cause chronic larynge-al irritation and hoarseness, the latter of which are also associat-ed with GERD. Asthma also is as-sociated with chronic cough and wheezing, both of which increase intra-abdominal pressure, which can theoretically result in pushing gastric contents up through the lower esophageal sphincter into the esophagus aggravating GERD.

Diagnosis of GERD is primarily based on a detailed history since it is impossible to confirm the diag-nosis with a pH probe and/or en-doscopy in all individuals with this disease (Figure 2). When complica-tions are suspected, a gastroenter-ologist consultation is indicated.

Treatment (Figure 3) includes life-style changes, i.e., avoiding large meals, maintaining ideal weight, not eating meals three hours be-fore retiring, not lying down within two hours after meals, elevating the head of the bed with 6-inch blocks or using a foam wedge to el-evate the trunk and head. Avoiding acid-containing foods, carbonated beverages and fatty foods also may be beneficial. Medications include H2 blockers, proton pump inhib-itors and prokinetic agents, the latter for individuals with delayed gastric emptying. GERD common-

potheses are proposed to explain this association; asthma bronchos-pasm is attributed to aspiration or reflux of gastric contents into the trachea, whereas the second im-plicates vagal reflexes mediated through stimulation of esophageal mucosal receptors by a low pH and distention. Both mechanisms prob-ably contribute to asthma in vary-ing degrees.

Double-blind controlled stud-

ies demonstrate that treatment of asymptomatic GERD does not improve asthma in adults or chil-dren; however, other controlled studies show that GERD-treated subjects with asthma and sympto-matic GERD experience improved asthma quality-of-life and have a reduced number of asthma exacer-bations, while there are question-able effects on asthma symptoms, albuterol use, and pulmonary func-tion. A Cochrane review of con-


TABLE 1

GERD Symptoms and Signs *

GastroesophagealHeartburn, chest/epigastric/cervical pain, water brash, belching, indigestion, nausea/vomiting/hematemesis

Respiratory Cough, wheeze, dyspnea, hemoptysis

LaryngealHoarseness, throat clearing, sighing dyspnea, irrita-tion, globus, voice changes, soreness

Nasal Congestion, itching, sneezing, soreness

Sinuses Headache, pressure, purulent discharge

Ears Otalgia

Teeth Loss of dental enamel

* Reproduced from Theodoropoulos DS, Lockey RF, Boyce HW Jr. Gastroesophageal re-flux and asthma: a review of pathogenesis, diagnosis, and therapy. Allergy. 1999;54:651-661, with permission from Wiley-Blackwell.

Figure 1 Factors which contribute to or cause GERD.A. Defective clearance of esoph-

ageal contents secondary to reduced salivary and esophageal submucosal gland secretion and ineffective peristalsis

B. Lower esophageal dysfunction with prolonged and inappropri-ate relaxations of the sphincter with reduction in basal lower esophageal sphincter pressure and tone

C. A hiatal hernia may compro-mise lower esophageal function causing gastric contents to be trapped above the diaphragm exacerbating reflux

D. Delay of gastric emptying may increase gastric contents available for reflux into the esophagus

E. Various illnesses, such as asthma, which are associated with chronic cough and expiratory straining during breathing, can increase intra-abdominal pressure, pushing gastric contents into the esophagus

D

E

A

BC

Pyloric Opening & Sphincter

Esophagus

Lower Esophageal Sphincter

Hiatal Hernia

Diaphragm

StomachDuodenum

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Figure 2 Diagnosis of GERD. (Modified from Theodoropoulos DS, Lockey RF, Boyce HW Jr. Gastroesophageal reflux and asthma: a review of pathogenesis, diagnosis, and

therapy. Allergy. 1999;54:651-661, with permission from Wiley-Blackwell.)


ly resolves by age 4 years in most children. When such resolution does not occur, treatment is similar to adults. Rarely, anti-reflux sur-gery is indicated.

Another problem, laryngopharyn-geal reflux, believed to be second-ary to the regurgitation of gastric content into the laryngeal phar-ynx, can result in laryngopharyn-geal and upper airway symptoms. Laryngopharyngeal reflux is also a co-morbid condition for asthma, if for no other reason, for the cough associated with such reflux. Also, upper airway disease is commonly associated with asthma, and docu-mented GERD is associated with a variety of different laryngeal and upper airway symptoms.

In summary, regardless of wheth-er there is a true association with GERD, i.e., that GERD can exacer-

Suspected GERD (see Table 1)

Pharyngolaryngoscopy Negative

Positive 24-h pH study Negative

Improvement 3-month therapeutic trial (See Figure 3) Poor response

Maintenance treatment

Other causes

Gastroenterology consult, endoscopy

? 24-h pH study to confirm acid suppression

Inadequate acid suppression

Adequate acid suppression

Adjust dose of medication

Other causes

Lifestyle changes and antacids

H2-receptor antagonists:

If unsuccessful, double dose or adminis-ter above doses four times a day

Change treatment to proton pump inhibitor:

If unsuccessful, double dose ½ hour be-

fore breakfast. If still symptomatic, double dose ½ hour before breakfast with single

dose ½ hour before dinner

bate asthma, or the converse, that asthma can exacerbate GERD, both seem reasonable because of the close association of the esopha-gus with the trachea and lungs and the similar embryologic derivation of the nervous system shared by both. Regardless, treating sympto-matic GERD in any patient, particu-larly those with asthma, is essential to prevent complications from GERD, as well as to increase the quality-of-life of the patient with or without asthma.

KEY REFERENCES1. Havemann BD, Henderson CA,

El-Serag HB. The association be-tween gastro-oesophageal reflux disease and asthma: a systematic review. Gut 2007;56:1654-1664.

2. Theodoropoulos DS, Ledford DK, Lockey RF, Pecoraro DL, Rod-riguez JA, Johnson MC, et al. Prevalence of upper respiratory symptoms in patients with symp-tomatic gastroesophageal reflux disease. Am J Respir Crit Care Med 2001;164:72-76.

3. Littner MR, Leung FW, Ballard ED 2nd, Huang B, Samra NK; Lansopra-zole Asthma Study Group. Lanso-prazole Asthma Study Group. Ef-fects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life and pulmonary function in adult asth-matic patients with acid reflux symptoms. Chest 2005;128:1128-1135.

4. Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996;100:395-405.

5. Ledford DK, Lockey RF. Asthma and comorbidities. Curr Opin Aller-gy Clin Immunol 2013;13:78-86.Figure 3 Maintenance treatment for

GERD. (Modified from Theodoropoulos DS, Lockey RF, Boyce HW Jr.

Gastroesophageal reflux and asthma: a review of pathogenesis, diagnosis, and

therapy. Allergy. 1999;54:651-661, with permission from Wiley-Blackwell.)

98


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ma • There is a conflict in the literature surrounding the asthma-related

risk of cardiovascular disease identified in large, longitudinal epidemiologic studies

• Relationships of asthma and cardiovascular disease seem to be stronger in women

• A common mechanism may contribute to allergies and atherosclerosis and systemic inflammation associated with asthma may adversely affect cardiovascular function

• Decreased pulmonary function, increased airway infection, and use of β2-agonists may increase the risk of cardiovascular disease

• Patterns of risks of myocardial infarction are similar between inhaled short-acting β2-agonists, long-acting β2-agonists and inhaled corticosteroids

Some studies report a significant association of asthma with cardio-vascular disease, but there is a con-flict in the literature surrounding the asthma-related risk of cardio-vascular disease identified in large, longitudinal epidemiologic studies.

Adult-onset asthma is associated with increased carotid atheroscle-rosis in women, and patients with bronchial hyperresponsiveness to methacholine demonstrated increased carotid intima–media thickness. Relationships between asthma and cardiovascular dis-ease in women seem to be stronger than those observed in men (Fig-ure 1). In general, allergic disease is more common in women after adolescence and it is thought that sex hormones modulate immune response. Estrogen is considered to increase humoral immunity. Be-ing female slightly increases the association of all cardiovascular diseases, mainly heart failure, but not angina, coronary disease and acute or old myocardial infarc-tion, with asthma. In contrast to females, males present with a pos-itive association between asthma and angina and coronary disease, but a negative association with acute or old myocardial infarction. An increase in age results in a pro-

gressive increase in the prevalence of the diagnosis of cardiovascular disease and hypertensive disease. Apparently, the smoking habit does not modify the prevalence of cardiovascular disease, compared to the general population.

A common mechanism may con-tribute to allergies and athero-sclerosis. IgE is itself potentially proatherogenic through actions on mast cells and platelets, although epidemiological studies indicate that atopy may be an independent protective factor against myocar-dial infarction. In any case, asth-ma and atherosclerosis occur on a

background of inflammation. Ani-mal studies have shown increased myocardial vulnerability in rabbits with systemic allergy and asthma. It has been suggested that airway allergen exposure results in im-paired vasodilatory response of the aorta in a murine model of pulmo-nary allergic response. This finding suggests that systemic inflamma-tion associated with asthma may adversely affect cardiovascular function. Actually, systemic in-flammation occurs in asthma, with an increase in circulating proin-flammatory cytokines, such as in-terleukin IL-6 and tumor necrosis factor-α and also in high-sensibility

CARDIOVASCULAR DISEASES AND ASTHMA6

Ke y m e ssag e s

Mario Cazzola University of Rome “Tor Vergata”

Italy

Cardiovascular diseases and asthma

99


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Cardiovascular diseases and asthma

C-reactive protein, likely because of the systemic dissemination of lo-cal lung inflammation leading to an overspill effect (Figure 2). This sys-temic component could feed back into and perpetuate the original lo-cal reaction and lead to the devel-opment of distant local reactions.

However, the role of systemic in-

flammation in asthmatic patients is still unclear and, consequently, debated. Asthma is a long-term inflammatory status complicated by decreased pulmonary function, increased airway infection, and use of β2-agonists. These factors may increase the risk of cardiovascular disease. Patterns of risks of myo-cardial infarction are similar be-

Figure 1 The association between asthma and cardiovascular comorbidities in Italy. (This article was published in Respir Med, 106, Cazzola M, Calzetta L, Bettoncelli G, et al, Cardiovascular disease in asthma and COPD: a population-based retrospective

cross-sectional study, 249-56, Copyright Elsevier 2012.)

Figure 2 The inflammation in the lung ‘spills over’ into the systemic circulation to produce systemic effects, such as cardiovascular complications.

tween inhaled short-acting β2-ag-onists, long-acting β2-agonists and inhaled corticosteroids. It is likely that the initial presentation with symptoms evoking asthma (dysp-noea presumably) is, in a large pro-portion of cases, the appearance of ischaemic heart disease. None-theless, it is noteworthy that some epidemiological studies have been unable to register concrete associ-ation of asthma with acute or pre-vious myocardial infarction.

KEY REFERENCES1. Cazzola M, Calzetta L, Betton-

celli G, Cricelli C, Romeo F, Ma-tera MG, et al. Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study. Respir Med 2012;106:249-256.

2. Cazzola M, Calzetta L, Bettoncel-li G, Novelli L, Cricelli C, Rogliani P. Asthma and comorbid medical illness. Eur Respir J 2011;38:42-49.

3. Cazzola M, Segreti A, Calzetta L, Rogliani P. Comorbidities of asth-ma: current knowledge and future research needs. Curr Opin Pulm Med 2013;19:36-41.

4. Iribarren C, Tolstykh IV, Miller MK, Sobel E, Eisner MD. Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts. Am J Epidemiol 2012;176:1014-1024.

5. Khan UI, Rastogi D, Isasi CR, Coupey SM. Independent and synergistic associations of asthma and obesity with systemic inflam-mation in adolescents. J Asthma 2012;49:1044-1050.

6. Warnier MJ, Rutten FH, Kors JA, Lammers JW, de Boer A, Hoes AW, et al. Cardiac arrhythmias in adult patients with asthma. J Asthma 2012;49:942-946.

IL-6, TNF-α

CRP

IL-6

Atheromaplaque

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ma • Foods can induce asthmatic reactions in patients with food allergy

• Patients with both asthma and food allergy are at risk of food-induced anaphylaxis

• Food allergy often precedes asthma and is a risk factor for its development

• Both being chronic allergic disorders, asthma and food allergy often go together

• Cross-reactive IgE of asthmatic patients with seasonal allergic rhinitis can cause subsequent food allergy

Food allergy (FA) is an adverse re-action to food caused by an over-reaction of the immune system that occurs each time a food is consumed. These reactions can be immune responses mediated by IgE antibodies, by immune cells, or by a combination of both. Food allergies are however most com-monly caused by IgE antibodies, and are characterized by acute onset of symptoms (usually within minutes to a few hours) following the ingestion of an implicated al-lergenic food. Symptoms can in-volve the skin, the gastrointestinal tract, the cardiovascular system including life-threatening ana-phylactic shock, and of relevance at this place, the respiratory tract including asthmatic symptoms. FA is estimated to affect 3-8% of chil-dren and 1-5% of adults, but con-siderable geographic differences exist also with respect to the type of foods involved. FA is often seen together with asthma, especially in infancy.

THE LINK BETWEEN FOOD ALLERGY AND ASTHMAFirstly, asthma can be one of the manifestations of an allergic reac-tion to food (Figure 1). Also, food additives, especially sulphites and monosodium glutamate, have been

reported to trigger asthma. Be-sides consumption of food, inhala-tion of cooking vapours of especial-ly fish, shellfish and eggs, is known to potentially cause asthmatic symptoms, and inhalation of wheat flour may cause occupational asth-ma in bakers.

Secondly, patients that have both asthma and food allergy have a higher risk to develop severe ana-phylactic reactions when exposed to the food they are allergic to (Fig-ure 2). Therefore, these patients need to be particularly cautious in avoiding the culprit foods.

Thirdly, sensitization (IgE) to food and clinical FA often precede the development of asthma (Figure 3). This sequence of appearance, often referred to as the “atopic

march”, points towards a common genetic predisposition for both dis-eases. A whole spectrum of gene polymorphisms has been implicat-ed in the development of asthma, illustrating the complex multi-fac-torial nature of the genetic predis-position of this disease. Far less is known about gene polymorphisms with relevance for FA. Recently a polymorphism in a gene coding for a protein involved in the integrity of the skin barrier was reported to be a risk factor for FA in patients that also have asthma.

Fourthly, food allergy not only precedes asthma but both chronic allergic disorders often also stick together (Figure 3). Although some food allergies like to milk and egg are outgrown by the majority of

FOOD ALLERGY AND ASTHMA7

Ke y m e ssag e s

Ronald van Ree Academic Medical Center

Netherlands

Antonella Muraro University of Padua

Italy

Food allergy and asthma

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children before the age of five, most other common food allergies such as to peanut and tree nuts are usually persistent and are still present when asthma develops.

Lastly, asthma with seasonal al-lergic rhinitis (hay fever) induced by tree and/or grass pollen can also precede instead of follow the development of FA (Figure 4). Al-though most pollen allergies pres-ent as hay fever, some patients develop asthma as well. In many of those patients some years after the onset of their pollen allergy, also symptoms of FA start devel-oping. This phenomenon can be explained by pollen-induced IgE antibodies cross-reacting to foods. The most well-known example of

such cross-reactivity is observed in patients with birch pollen aller-gy. Their IgE antibodies cross-react with fruits like apple and cherry, with tree nuts like hazelnut and with some vegetables like carrot and celeriac. Symptoms of FA in such patients are almost always mild and limited to the oral cavity.

In conclusion, asthma is often ac-companied by FA but the basis of this co-morbidity is diverse.

KEY REFERENCES1. Burks AW, Tang M, Sicherer S, Mu-

raro A, Eigenmann PA, Ebisawa M, et al. ICON: food allergy. J Allergy Clin Immunol 2012;129:906-920.

2. Koplin JJ, Martin PE, Allen KJ. An update on epidemiology of ana-phylaxis in children and adults.

Curr Opin Allergy Clin Immunol 2011;11:492-496.

3. Illi S, von Mutius E, Lau S, Nickel R, Grüber C, Niggemann B. The nat-ural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004;113:925-931.

4. McAleer MA, Irvine AD. The mul-tifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 2013;131:280-291.

5. Vieths S, Scheurer S, Ballmer-We-ber B. Current understanding of cross-reactivity of food aller-gens and pollen. Ann N Y Acad Sci 2002;964:47-68.

6. Calvani M, Cardinale F, Martelli A, Muraro A, Pucci N, Savino F, et al. Risk factors for severe pediatric food anaphylaxis in Italy. Pediatr Allergy Immunol 2011;22:813-819.

Figure 1 Asthma can be one of the manifestations of an allergic reaction to food. FA - food allergy.

Figure 2 Patients that have both asthma (A) and food allergy have a higher risk to develop severe anaphylactic reactions

when exposed to the food they are allergic to.

Figure 3 Sensitization (IgE) to food and clinical FA often precede the development of asthma (the “atopic march”).

Figure 4 Asthma induced by tree and/or grass pollen can precede the development of FA (oral allergy syndrome).

Food allergy and asthma

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disease and results from the complex interplay between defects in skin barrier function, environmental and infectious agents, and immune abnormalities

• Severe AD beginning early in life is a high-risk phenotype for the development of asthma

• Specific IgE is associated with food or environmental allergens, which may be relevant trigger factors for both AD and asthma

• The disturbed expression of the skin barrier protein filaggrin is linked to childhood AD and the subsequent development of asthma

• Urticaria is often a presenting feature of anaphylaxis, involving respiratory difficulty due to inspiratory stridor, expiratory wheeze or both. Acute urticaria by definition does not involve respiratory distress

• Bronchial hyperreactivity has been reported in some patients with chronic spontaneous and inducible patterns of urticaria

• Kinin-induced angioedema involving the airways in hereditary or acquired angioedema and angiotensin converting enzyme inhibitor-induced angioedema requires emergency treatment and may be fatal

Atopic dermatitis (AD) is a com-mon inflammatory skin disorder, characterized by pruritus, a chron-ic relapsing course, a distinctive distribution of eczematous skin lesions (Figure 1) and a personal or family history of atopic diseases in-cluding asthma. It results from the complex interplay between defects in skin barrier function, environ-mental and infectious agents, and immune abnormalities.

During the last decades a marked increase in the frequency of AD has been observed and it is now the most frequent inflammatory skin disease, with a childhood prev-alence of more than 10% in most European countries. The manifes-tation of AD in childhood is great-er in families with a higher income and a more privileged lifestyle. This

may be due to reduced incidence of infections in early childhood and reduced contact with agents that elicit Th1 associated cellular im-mune responses. Of note, differ-ences in prevalence of respiratory allergic diseases often do not par-allel prevalence of AD in larger ep-idemiologic studies, which points to independent risk and manifesta-

tion factors being critical for both atopic diseases.

AD often begins in early infan-cy. Severe AD beginning before 6 months of age is a high-risk phe-notype for the development of asthma, especially in boys. Further-more, AD is linked to food allergy and children with multiple severe food allergies are also at a higher

SKIN AND LUNG: ATOPIC DERMATITIS, URTICARIA AND

ASTHMA8

Ke y m e ssag e s

Thomas Werfel Hannover Medical School

Germany

Clive Grattan Norfolk & Norwich University

Hospital, UK

Skin and lung: atopic dermatitis, urticaria and asthma

Figure 1 Flexural dermatitis on the right arm and disseminated eczema on the trunk in a male adolescent patient

with atopic dermatitis.

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Like in allergic asthma, there is an overexpression of Th2 cytokines in lymphatic organs, circulating T-cells and the acute phase of cu-taneous inflammation in many patients with AD. This is close-ly linked to the regulation of IgE, which is higher than normal in 80% of all patients. Specific IgE is com-monly associated with food or en-vironmental allergens, which may be relevant trigger factors both for AD, rhinitis and / or asthma in indi-vidual patients.

Studies of the gene of encoding the skin barrier protein filaggrin have shown the link between ear-ly childhood eczema and the sub-sequent development of asthma

which may, in part, be due to de-fective epidermal barrier function leading to increased allergen sensi-tization (Figure 2).

It appears that different disease mechanisms are important for dif-ferent subgroups of patients suf-fering from AD. Described genetic polymorphisms in AD involve me-diators of atopic inflammation on different chromosomes. Some, but not all of these may also play a role in respiratory atopy.

Besides the “allergic” variant of AD there is a non-allergic form which is found in 20% of diseases with the typical clinical appearance of the disease. In this respect, AD resem-bles asthma, which also has allergic and non-allergic variants.

Figure 2 Filaggrin mutations and atopic dermatitis and asthma. (Adapted from Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and

allergic diseases. N Engl J Med 2011;365:1315-1327.)


Asthma(overall risk)

Healthy skin

Allergen

Filaggrin-deficient skin

Allergen• Impaired skin barrier• Increased skin-surface pH• Increased allergen priming• Decreased hydration of

stratum corneum• Decreased resistance to

staphylococcus

Filaggrin mutation

Management of AD exacerbations is a therapeutic challenge, as it re-quires efficient short-term control of acute symptoms, without com-promising the overall management plan, which is aimed at long-term stabilization, flare prevention, and avoidance of side effects. Exacer-bation may sometimes uncover relevant provocation factors, for example food or inhalant allergy, or infection, which in turn may also lead to worsening of asthma (Fig-ure 3).

The prognosis for patients with AD is generally favourable, but patients with severe, widespread disease and concomitant asthma are likely to experience poorer out-comes.

Urticaria does not characteristical-ly involve the respiratory tract, but there are a few situations where there is overlap. The first is ana-phylaxis where urticaria involving wheals, angioedema or both may be the initial presentation of an acute systemic illness defined by respiratory difficulty, hypotension or both, with or without gastroin-testinal symptoms. Anaphylaxis is often due to an immediate hyper-sensitivity response to a food, drug or sting, but may be non-allergic. The boundaries between anaphy-laxis and acute urticaria may not be clear at the time, particularly when food allergy presents with general-ized urticaria. By definition, acute urticaria does not present with systemic symptoms, is continuous (daily or almost daily eruptions itchy skin or mucosal swellings) and lasts for up to 6 weeks, but usually resolves over 10 to 14 days.

Chronic urticaria is not associated with asthma and is hardly ever due to IgE-mediated allergies (except perhaps in very young children with undetected food allergies)

Asthma in the absenceof atopic dermatitis

Asthma in the presenceof atopic dermatitis

Odds ratio 1.5

No increased risk

Odds ratio, 3.3

Odds ratio 3.1

eczema/spongiosis

Langerhans cell activation and migration

dermal mononuclear

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Figure 4 Kinin formation and breakdown relevant in urticaria. LMWK, low molecular weight kininogen; HMWK, high molecular weight kininogen;

kallidin, Lys-bradykinin; B2R, bradykinin receptor 2 – receptor for bradykinin; B1R, bradykinin receptor 1 – receptor for the active metabolite of bradykinin

(bradykinin 1-8 or des arginine bradykinin); ACE-angiotensin converting enzyme

Figure 3 Trigger factors of atopic dermatitis.


Atopic dermatitis

Hormones

Food

Inhalant allergens

Bacterial colonization of the skin

Irritating substances

Climate

Psychological stress

Systemic infections

although it may occur as an appar-ently independent illness in atopic patients. Around 30% of patients with chronic spontaneous urticar-ia have functional autoantibodies that release histamine from skin mast cells and basophils, so it is surprising that the respiratory tract is not overtly affected. One study concluded that bronchial hyperresponsiveness is a common feature in patients with active chronic urticaria. Twenty six adults with chronic spontaneous urticar-ia were assessed with respiratory function tests and methacholine provocation. Two had asthma on baseline pulmonary function tests and twenty others (77%) showed bronchial hyperresponsiveness on methacholine challenge. Bronchial hyperresponsiveness has also been demonstrated in patients with cho-linergic urticaria and symptomatic dermographism.

Spontaneous and inducible urti-carias are believed to be caused by mast cell and basophil media-tor release (primarily histamine). By contrast, there is a small, but very important group of patients who present with angioedema without wheals due to kinin gen-eration. These include hereditary angioedema, acquired angioede-ma associated with lymphoprolif-erative disease or autoantibodies against C1 esterase inhibitor, and angiotensin converting enzyme in-hibitor (ACEI)-induced angioede-ma. The pathways involved with ACEI-induced angioedema are complicated (Figure 4). Kinin-in-duced angioedema often affects the respiratory tract from the lips to the larynx and may be fatal. The specific bradykinin 2 receptor re-ceptor antagonist, icatibant, offers a specific treatment for these pa-tients presenting acutely with res-piratory tract involvement.

KEY REFERENCES1. Akdis M. The cellular orchestra in

skin allergy; are differences to lung and nose relevant? Curr Opin Aller-gy Clin Immunol 2010;10:443-451.

2. Bieber T, Cork M, Reitamo S. At-opic dermatitis: a candidate for disease-modifying strategy. Aller-gy 2012;67:969-975.

3. Werfel T. The role of leukocytes, keratinocytes, and allergen-spe-cific IgE in the development of at-opic dermatitis. J Invest Dermatol 2009;129:1878-1891.

4. Asero R, Madonini E. Bronchial hyperresponsiveness is a common feature in patients with chronic urticaria. J Investig Allergol Clin Im-munol 2006;16:19-23.

5. Petelas K, Kontou-Fili K, Gratziou C. Bronchial hyperresponsiveness in patients with cholinergic urti-caria. Ann Allergy Asthma Immunol 2009;102:412-421.

6. Henz BM, Jeep S, Ziegert FS, Niemann J, Kunkel G. Dermal and bronchial hyperreactivity in urti-carial dermographism and urticaria factitia. Allergy 1996;51:171-175.

LMWK

Kallidin

HMWK

BRADYKININ

B2R

BRADYKININ (1-8)

tissue Kallikrein

B1R

BRADYKININ (1-7)

BRADYKININ (1-5)

Aminopeptidase P

Aminopeptidase PNeutral endopeptidase

ACE (kininase II)

Carboxypeptidase N (kininase 1)

ACE

Section C

MAJOR CURRENT PROBLEMS

IN ASTHMA

* Unmet needs in asthma * Asthma exacerbations* Severe asthma* Adherence to asthma treatment* Social determinants of asthma* Inequities and asthma

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• There is a global burden of limited access to drugs and good patient care in underdeveloped regions

• There is no established way towards a prevention of asthma • There is no established curative treatment • Biomarkers to subgroup patients, predict outcomes and follow

therapy response are needed• Vaccine development against viruses that trigger exacerbations

should be supported• Patient-tailored treatment should be implemented• Next generation global guidelines that consider individual needs,

regional differences and disease subgroups are needed• A worldwide registry and regional biobanks for asthma are

needed

Unmet needs in asthma cover al-most every aspect of the disease. They can be classified as unmet needs due to missing scientific knowledge, related to patient care and chronic nature of the disease, and related to socioeconomic fac-tors.

Knowledge on pathomechanisms of asthma has several essential gaps (Table 1). One main histor-ical reason was disregarding its complexity and consideration of asthma as a single disease entity. It is now becoming clear that the complex interplay between the en-vironment and the immune system in combination with the response of the tissue cells ultimately de-termines the development and ex-pression of asthma with different phenotypes and endotypes. Par-ticularly, the intrauterine and life-long exposure to every facet of the environment, the so called expos-ome and its role in activation and tolerance thresholds of the tissues and the immune system represent major targets for research.

Asthma prevention includes pri-mary prevention to prevent the development of the disease and secondary prevention to prevent asthma development in subjects with atopy. There is no established

way of primary prevention of asth-ma and a series of questions in the public remain unanswered such as, if parents have asthma, will the child also develop asthma? Is there any way to avoid this? If asthma develops, will it be possible to out-grow asthma?

A global unmet need is the inter-national and regional burden of access to drugs and good patient care. Asthma prevalence is globally increasing in parallel to urbaniza-tion and economic development, however individuals with low so-cio-economic status, minorities

and urban populations are deeply affected. Low socio-economic sta-tus individuals are highly exposed to triggers such as environmental pollutants, poor housing, indoor allergens, and psychosocial stress-ors. It is essential to develop global approaches to fight with inequities, educational deficits and delivery of high quality asthma care in the whole World to improve individual patient care.

The possibility of cure in asthma is a fundemental issue for research, because the currently used med-ications only temporarily relieve

Cezmi A. Akdis Swiss Institute of Allergy and Asthma Research

Davos, Switzerland

UNMET NEEDS IN ASTHMA 1

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Unmet needs in asthma

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symptoms by suppressing inflam-mation. A long-term cure for al-lergic asthmatic patients can be achieved through the use of aller-gen immunotherapy, which has a disease-modifying effect and might also lead to decreased re-quirements for anti-inflammato-ry and symptomatic medications. However, only a fraction of asthma patients respond successfully to al-lergen-immunotherapy and there is no established clinical criteria or a predictive biomarker for the se-lection of these patients.

Unmet needs in patient care in asthma remain essential problems similar to many chronic diseases (Table 2). It is expected that pa-tient-tailored therapies will im-prove and become a standard in patient care one day. Accordingly, problems in adherence to treat-ment, self management, preven-tion of exacerbations, develop-ment of severe asthma, side effects of medications are expected to di-minish in time.

Biomarkers to diagnose, subgroup and follow patients represent an important need in most of the chronic diseases. We have no bio-logical indicators that accurately predict the development of asth-ma, identify high risk children and the disease course of an asthmatic patient. In addition, there is very few indicators for the selection of a certain therapy responsive pa-tients, such as allergen-immuno-therapy or a treatment with a bio-logical immune response modifier (Table 3). Apparently, novel biolog-icals should be developed together with their biomarker for the selec-tion of responsive patients.

Asthma exacerbations are linked with high morbidity, significant mortality and represent an out-standing problem in the clinical management of asthma. They con-stitute the biggest immediate risk and anxiety to patients and their families, linked to continuous de-cline in lung function over time and generate a huge financial burden in health care systems. Targeting res-

TABLE 1

Major research gaps for asthma

• Immunological basis of asthma epidemic

• Innate immune response and tissue response to exposome such as molecules that are coexposed with allergens, microbes, pollutants

• Role of novel subsets of T cells, B cells and innate lymphoid cells in asthma development

• Indepth analysis of individuals who outgrow from asthma

• Epithelial barrier function and its role in asthma development and chronicity

• Mechanisms of development of immune tolerance to allergens and novel ways to induce this

• Understanding epigenetic regulation of the asthmatic inflammation

• Development of novel biologicals for treatment

• Identification of novel biomarkers for endotyping patients for the prediction of treatment response and prognosis

• Development of immunological registries and disease-specific biobanks

TABLE 2

Unmet needs in patient care

• Patient adherence

• Inequities in asthma care in the whole World

• Education of patients and careers

• Self management of patients

• Prevention of asthma exacerbations

• Severe asthma patients

• Side effects of medications

• Better drug delivery systems

• Patient tailored therapies

TABLE 3

Next steps in diagnosis of asthma endotypes

• Improvement of molecular diagnostics methods

• Discovery of surrogate biomarkers

• Easy and standardized tests for cellular diagnosis from peripheral blood

• Easy and standardized analysis of exhaled breath condensate and sputum

• Development of point of care assays and devices

• Development of tests for prediction of exacerbations and treatment response

• Development of tests for the analysis of immune response to respiratory viruses

piratory viruses with vaccines will be one of the most efficient ways to prevent exacerbations.

Severe asthma represents one of the most significant burdens of all diseases from all perspectives of affected patients and health care system. These individuals use a large proportion of public health resources devoted to the treat-

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TABLE 4

Problems in drug development for asthma

• There is a huge amount of missing knowledge in the complexity of the whole disease spectrum with highly complex molecular mechanisms and multiple subgroups

• Almost no biomarkers exist for patients’ selection, therapy response, and for prediction of disease development

• There is limited space to improve the patients response over existing therapies, because currently used inhaled steroid and β-adrenergic agonist combination therapy is effective and relatively inexpensive

• Most drugs that are effective in mouse models have failed in clinical trials, because currently available animal models do not represent human asthma

• Individual outcomes are different due to molecular complexity and cannot be distinguished using a bulk approach

• Most novel biologicals are unlikely to be effective, when used alone and it is not possible to study the combination of two new biologicals that may potentiate each other until one of them is approved

ment of asthma and more effective therapies are urgently required. Novel drugs are needed for severe asthma. Unfortunately, drug devel-opment programs have failed in the last several decades due to multi-ple reasons summarized in Table 4.

Guidelines developed for asthma have grouped all asthma pheno-types and endotypes together as if they are a single uniform disease. The heterogeneity of asthma, de-fining of asthma subgroups and their particular needs have not been taken into account. Region-al needs and differences have not been deeply considered and input of patients themselves have been neglected. An advance for cur-rently existing guidelines was the implementation of evidence-based medicine as a movement toward a more structured assessment of clinical knowledge and was provid-ing a method of evaluating health effects and economic impact. Next generation global guidelines will

have to appreciate the needs of in-dividuals, consider regional differ-ences, different disease subgroups with a scientific approach.

KEY REFERENCES1. Papadopoulos NG, Agache I,

Bavbek S, Bilo BM, Braido F, Car-dona V, et al. Research needs in al-lergy: an EAACI position paper, in collaboration with EFA. Clin Transl Allergy 2012;2:21.

2. Agache I, Akdis C, Jutel M, Vir-chow JC. Untangling asthma phe-notypes and endotypes. Allergy 2012; 67:835-846.


4. Carlsten C, Melén E. Air pollution, genetics, and allergy: an update. Curr Opin Allergy Clin Immunol 2012;12:455-460.

5. Gavala ML, Bertics PJ, Gern JE. Rhinoviruses, allergic inflamma-tion, and asthma. Immunol Rev

2011;242:69-90.

6. Ring J, Akdis C, Behrendt H, Lauener RP, Schäppi G, Akdis M et al. Davos declaration: allergy as a global problem. Allergy 2012; 67:141-143.

7. Akdis CA. Therapies for allergic inflammation: refining strate-gies to induce tolerance. Nat Med 2012;18:736-749.

8. Kupczyk M, Wenzel S. U.S. and European severe asthma co-horts: what can they teach us about severe asthma? J Intern Med 2012;272:121-132.

9. Yonas M, Lange N, Celedon J. Psy-chosocial stress and asthma mor-bidity. Curr Opin Allergy Clin Immu-nol 2012;12:202-210.

10. Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al. Update on allergy immunothera-py: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/ PRACTALL consen-sus report. J Allergy Clin Immunol 2013;131:1288-1296.

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• Acute exacerbations of asthma require urgent treatment to prevent a serious outcome and generate the greatest financial burden for health care systems

• Asthma exacerbations rate reported in clinical trials ranges from 0.3 - 0.9 /patient /year; surveys of ‘real life’ asthma patients indicate a higher incidence, particularly in poorly-controlled asthmatics

• Factors reported to be associated with frequent exacerbations include poor asthma control, respiratory infections, female sex, obesity, psychopathology, chronic sinusitis, gastro-oesophageal reflux and obstructive sleep apnoea

• Viral infection and allergy interact to increase the risk of an exacerbation

• Patient education, self-management plans and most of the anti-asthmatic drugs have been convincingly shown to reduce exacerbations requiring hospitalisation

• Vaccination against respiratory viruses remains an attractive and potentially effective strategy

The Global Initiative for Asthma (GINA), defines acute exacerba-tions of asthma as “episodes of progressive increase in shortness of breath, cough, wheezing, or chest tightness, or some combination of these symptoms, accompanied by decreases in expiratory airflow that can be quantified by measurement of lung function.” They are a marker of severe loss of control and require urgent treatment to prevent a se-rious outcome. Exacerbations con-stitute the greatest immediate risk to patients, are associated with ac-celerated decline in lung function over time, significant anxiety to patients and family members alike, and generate the greatest financial burden for health care systems.

Airflow obstruction during exac-erbations stems from a combina-tion of concentric smooth muscle contraction, airway wall oedema, airway inflammatory cell infiltra-tion and luminal obstruction with mucus and cellular debris (Figure 1). Exacerbations vary greatly in speed of onset, intensity and in time to resolution both between patients and for individual patients.

EPIDEMIOLOGY OF ASTHMA ExACERBATIONSThe frequency with which asthma exacerbations are reported in the

clinical trial literature ranges from 0.3 - 0.9 /patient /year and varies according to the definition of ex-acerbation used and the severity and/or level of disease control of the asthmatic population being studied. However surveys of ‘real life’ asthma patients indicate that the incidence of exacerbations is much higher, particularly in poorly controlled asthmatics.

Additional factors reported to be

associated with frequent exacer-bations include female sex, obesity, psychopathology, chronic sinusitis, gastro-oesophageal reflux, res-piratory infections and obstructive sleep apnoea.

AETIOLOGY OF ASTHMA ExACERBATIONSSince the early 1960s, viral res-piratory tract infections have been reported as triggers for asthma exacerbations. Following the intro-

ASTHMA ExACERBATIONS2

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David J. Jackson Sebastian L. Johnston Imperial College

London, UK

Asthma exacerbations

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duction of polymerase chain reac-tion (PCR) technology in the 1990s a clear demonstration of this im-portant link has been repeatedly observed with rhinoviruses con-sistently highlighted as the most frequently detected pathogens (Figure 2). Influenza viruses and respiratory syncitial virus (RSV) as well as other respiratory viruses are less common, but well recog-nised precipitants.

A growing body of evidence sup-ports the view that viral infection and allergy interact to increase the risk of an exacerbation with the vi-rus acting as a cofactor along with environmental allergens to initiate an exacerbation to an extent that neither alone can achieve. The ap-parent synergy between respirato-ry viruses and exposure to sensitis-ing allergens has been reported in

both children and adults and sug-gests atopic asthma is associated with more severe illness following virus infection than asthma in the absence of allergic sensitisation (Figure 3).

Bacteria (in particular the atypical organisms Mycoplasma pneumoni-ae and Chlamydophila pneumoniae) have also been reported as contrib-utors to exacerbations however differences in sampling/diagnostic methodologies have led to incon-sistent results. Standard bacterial infection has recently been report-ed as important as viral in children under 3 years of age. Further stud-ies are required to confirm this and to investigate other ages. Other important but less common trig-gers include pollutants, smoking, and psychological factors.

PREVENTION OF ExACERBATIONSNon-pharmacologic approaches emphasised in recent years include the role of patient education and self-management plans, which have been convincingly shown to reduce exacerbations requiring hospitalisation. A large number of clinical trials have also shown the benefit of drug therapies in reduc-ing exacerbations including inhaled corticosteroid (ICS) treatment (with a combination of ICS and long-acting bronchodilators being more effective than ICS alone) as well as leukotriene receptor an-tagonists. In addition, monoclonal antibodies directed against IgE and the Th2 cytokines IL-5 & IL-13 have shown promise in selected asth-matics.

Finally, vaccination against respira-

Figure 1 Airway casts recovered from an asthmatic subject during an acute

exacerbation. (This article was published in Ann Allergy, 67, Lang DM, Simon RA, Mathison

DA, et al, Safety and possible efficacy of fiberoptic bronchoscopy with lavage in the

management of refractory asthma with mucous impaction, 324-330, Copyright Elsevier 1991.)

Figure 2 Respiratory viruses are the most common trigger for asthma exacerbations in both adults and children with rhinoviruses identified as the most frequently identified trigger (A). The September epidemic of asthma hospitalisation appears to reflect school children acting as

disease vectors spreading viral infections following the return to school after the summer holiday (B). (Reprinted from J Allergy Clin Immunol,

115/1, Johnston NW, Johnston SL, Duncan JM, et al, The September epidemic of asthma exacerbations in children: a search for etiology, 132-128, Copyright

2005, with permission from Elsevier.)


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tory viruses remains an attractive and potentially effective strategy. However, whilst influenza vaccina-tion in asthmatic patients is recom-mended, an effective vaccine for rhinovirus infection remains a long way off at present.

KEY REFERENCES1. From the Global Strategy for

Asthma Management and Pre-vention. Global Initiative for Asth-ma (GINA) 2012. Available from: www.ginasthma.org.

2. Peters SP, Jones CA, Haselkorn T, Mink DR, Valacer DJ, Weiss ST. Real-world Evaluation of Asthma Control and Treatment (REACT): findings from a national Web-based survey. J Allergy Clin Immu-nol 2007;119:1454-1461.

3. Minor TE, Dick EC, DeMeo AN, Ouellette JJ, Cohen M, Reed CE. Viruses as precipitants of asth-matic attacks in children. JAMA

1974;227:292-298.

4. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, et al. Community study of role of viral infections in exac-erbations of asthma in 9-11 year old children. BMJ 1995;310:1225-1229.

5. Green RM, Custovic A, Sander-son G, Hunter J, Johnston SL, Woodcock A. Synergism be-tween allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ 2002;324:763.

6. Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston SL, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen expo-sure increase the risk of asthma hospital admissions in children. Thorax 2006;61:376-382.

7. Simpson A, Tan VY, Winn J, Svensén M, Bishop CM, Heck-

erman DE, et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am J Respir Crit Care Med 2010;181:1200-1206.

8. Bisgaard H, Hermansen MN, Bønnelykke K, Stokholm J, Baty F, Skytt NL, et al. Association of bacteria and viruses with wheezy episodes in young children: pro-spective birth cohort study. BMJ 2010;341:c4978.

9. Lang DM, Simon RA, Mathison DA, Timms RM, Stevenson DD. Safety and possible efficacy of fiberoptic bronchoscopy with lavage in the management of refractory asthma with mucous impaction. Ann Aller-gy 1991;67:324-330.

10. Johnston NW, Johnston SL, Dun-can JM, Greene JM, Kebadze T, Keith PK, et al. The September ep-idemic of asthma exacerbations in children: a search for etiology. J Al-lergy Clin Immunol 2005;115:132-138.

Figure 3 Kaplan-Meier estimates of cumulative risk of hospital admission with wheeze or asthma during the first 8 years of life stratified on 5-class model. A - Age at first hospital admission for children who had a hospital admission with wheeze or asthma at any age. B - Age at first hospital admission among children who had a hospital admission after age 3 years. A sig-nificant increase in the risk of hospital admission with acute asthma is seen only among children in the multiple early class, but not among those in any of the other atopy classes. (Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. Simpson A, Tan VY, Winn J, et al. Beyond atopy: multiple patterns of sensitization in relation to

asthma in a birth cohort study. Am J Respir Crit Care Med 2010;181:1200-1206. Official journal of the American Thoracic Society.)


A B

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• It is comprised of 3 groups, each carrying different public health messages and challenges:

� Untreated severe asthma � Difficult to treat asthma � Treatment resistant severe asthma:

x Controlled on high dose medication x Not controlled on high dose medication

• Asthma severity is determined by the intensity and phenotype of the underlying disease.

• Risk factors for the development of severe asthma include factors associated with low pre-bronchodilator FEV1% predicted.

• All patients with severe asthma should be on age-appropriate high doses of inhaled corticosteroids and other controllers.

EPIDEMIOLOGY AND SCOPE OF THE PROBLEMAsthma is a global health problem resulting in approximately 250,000 deaths/ year, many of which result from severe asthma. Severe asth-matics (5 to 10% of all patients) impose a significant burden on healthcare utilization through unscheduled primary care visits, emergency room visits, hospitali-zations, days off work ⁄ school and a requirement for multiple asthma medications. In comparison with mild or moderate asthma, severe asthmatics are 15 times more likely to use emergency services and 20 times more likely to be ad-mitted to hospital. Severe asthma is generally associated with poor asthma control (defined by daily symptoms, poor quality of life and deteriorated lung functions) and increased risk of frequent severe exacerbations (or death) and/or chronic morbidity (including im-paired lung function or reduced lung growth in children) despite in-tensive treatment and/or adverse reactions to medications.

SEVERE ASTHMA DEFINEDThere are many definitions of se-vere asthma, but perhaps one of the best came about as a result of a World Health Organization

(WHO) meeting convened in 2009. The WHO panel stated that severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) Un-treated severe asthma: untreated either because of failure to make the diagnosis or because basic access to care or to medications are not available or affordable. (2) Difficult-to-treat severe asthma: asthma not adequately responding to prescribed treatment due to ad-herence issues, inappropriate or in-correct use of medications or other reasons. (3) Treatment-resistant severe asthma (also known as se-

vere, therapy-resistant asthma, or treatment refractory asthma). The last group includes asthma for which control is not achieved despite the highest level of recom-mended treatment and asthma for which control can be maintained only with the highest level of rec-ommended treatment which may result in untoward adverse effects from the therapeutic regimen.

Asthma severity is determined by the intensity and phenotype of the underlying disease, both of which may be characterized by patho-logical and physiological markers.

SEVERE ASTHMA3

Ke y m e ssag e s

Thomas B. Casale Creighton University

Omaha, USA

Severe asthma

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Severe asthma

However, it is important to recog-nize there are no current biomark-ers or even distinct physiological parameters that define severe asthma or its phenotypes. It is pos-tulated that the effectiveness of a given pharmacotherapy may be dependent on asthma phenotype and genetics with this heterogene-ity likely impacting the variable re-sponses to medications observed in severe asthma.

RISK FACTORS FOR SEVERE ASTHMAAlthough largely unknown, there are many factors known to influ-ence severe asthma development and persistence (Figure 1). Low pre-bronchodilator FEV1% of pre-dicted increases the risk of being classified as severe asthma. Thus, abnormalities in genes related to poorer lung functions, racial back-ground, male sex, sputum eosin-ophilia and personal smoking are likely to play a role. Other identi-fied risk factors include a history of pneumonia and secondhand tobac-co smoke exposure.

THERAPY OF SEVERE ASTHMAImproved care of severe asthma is a major unmet medical need. Op-timal therapy includes appropri-ate environmental modifications, management of comorbidities and pharmacotherapy, assuring ad-herence (Figure 2). According to the Innovative Medicine Initiative, all patients with severe asthma should be on high intensity asthma treatment defined as:

• 1000 mcg/day fluticasone equivalent combined with long acting beta-2- agonists or other controllers (adults)

• 500 mcg/day fluticasone equiva-lent (school-aged children)

• 400 mcg/day budesonide equiv-alent and oral leukotriene re-ceptor antagonists (pre-school children).

In patients unresponsive to this regimen and having a significant allergic component, the anti-IgE monoclonal antibody, omalizumab, may be added.

There are many therapies in devel-

opment for severe asthma. Howev-er several unanswered questions surround these novel treatments including:

• Will therapies be phenotype/en-dotype/biomarker driven?

• Which treatments will decrease symptoms and exacerbations and improve quality of life with a favorable risk/benefit ratio?

• Will any of the novel therapies truly be immunomodulators ca-pable of preventing the onset or reversing asthma pathophysio-logic changes?

KEY REFERENCES1. Kupczyk M, Wenzel S. U.S. and

European severe asthma co-horts: what can they teach us about severe asthma? J Intern Med 2012;272:121-32.

2. Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, con-trol, and exacerbations: document presented for the World Health Organization Consultation on Se-vere Asthma. J Allergy Clin Immu-

Figure 1 Factors influencing severe asthma, development and persistence. (Reproduced from Kupczyk M, Wenzel S. U.S. and European severe asthma cohorts: what can they teach us about severe asthma? J Intern Med 2012;272:121-132 with permission

from John Wiley and Sons, Inc.)

Severe asthma

Compliance adherence

Phenotype A

Rhino- sinusitis

Tobacco smoke

Viruses

Genetics

Allergen exposure

Obesity

Phenotype B

Phenotype C

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Figure 2 Severe asthma management paradigm.

Severe asthma

Manage Comorbidities

Appropriate Pharmacotherapy

Environmental Modification

Irritant Occupational Trigger

Allergen

Evidence-Based Decision Making

Cost- Effectiveness

Chronic Rhinosinisitis

ASA Sensitivity

GERDPhenotype Decision Making Pharmacogenetics

Disease Control

Achieve Goals

Morbidity Mortality

Economic Burden

Disease Variability

Monitoring Asthma Control

nol 2010;126:926-938.

3. Bush A, Zar HJ. WHO univer-sal definition of severe asthma. Curr Opin Allergy Clin Immunol 2011;11:115-121.

4. Bel EH, Sousa A, Fleming L, Bush A, Chung KF, Versnel J, et al. Diag-nosis and definition of severe re-fractory asthma: an international consensus statement from the In-novative Medicine Initiative (IMI). Thorax 2011;66:910-917.

5. National Asthma Education and Prevention Program. Expert Pan-el Report 3 (EPR-3): Guidelines for the Diagnosis and Manage-ment of Asthma-Summary Re-

port 2007. J Allergy Clin Immunol 2007;120:S94-138.

6. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, pla-cebo-controlled trial. Lancet 2012;380:651-659.

7. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Ar-ron JR, et al. Lebrikizumab treat-ment in adults with asthma. N Engl J Med 2011;365:1088-1098.

8. Polosa R, Casale T. Monoclonal antibodies for chronic refracto-ry asthma and pipeline develop-

ments. Drug Discov Today 2012; 17:591-599.

9. Jarjour NN, Erzurum SC, Bleecker ER, Calhoun WJ, Castro M, Com-hair SA, et al. Severe asthma: les-sons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Pro-gram. Am J Respir Crit Care Med 2012;185:356-62.

10. Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, et al. Omalizumab in severe allergic asthma inadequately con-trolled with standard therapy: a randomized trial. Ann Intern Med 2011;154:573-582.

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• Adherence to asthma treatment has been found to be globally poor

• Low adherence leads to increased morbidity and costs• Factors involved in poor adherence to treatment can be classified

as drug and non-drug related factors• Most of the non-drug related factors can be overcome by an

improved doctor - patient communication and educational interventions

Adherence to medical recommen-dations is defined by the extent to which the patient’s behavior matches agreed recommendations from the prescriber. The patient is free to decide whether to adhere to the doctor’s recommendations or not and failure to do so should not be a reason to blame the patient. Concordance describes the patient / prescriber relationship and the degree to which the prescription represents a shared decision, in which the beliefs and preferences of the patient have been taken into consideration.

Two types of non-adherence are described: intentional, usually due to lack of motivation, and non-in-tentional, which occurs when pa-tients/caregivers do not properly understand the prescription or the use of the medication, as well as when they forget or are unable to administer the inhaled medication. Usually, the attending physician measures the adherence to treat-ment, while lifestyle changes re-ceive less attention.

Several methods were used to measure adherence to treatment in asthma: patient or family re-ports, clinical judgment, weighing/dispensing of medication, electron-ic medication monitoring and bio-

chemical analysis.

Adherence to asthma treatment has been found to be poor global-ly. True adherence rates are lower than those reported by patients, and this should be considered first in cases of poor control of asthma. The outcome of non-adherence is loss of opportunities for patients to improve their health, loss of medi-cation by health-care systems, loss of working and school days. The financial perspective of non-adher-ence in asthma is impressive: ap-proximately £230 million of medi-cines are returned to pharmacies in the UK each year, with a great deal more disposed of by patients them-selves, while in the US non-adher-ence to medical regimens has been estimated to cost the US healthcare system $100 billion per year.

An epidemiological study called Asthma Insights and Reality in Ja-pan in 2011 (AIRJ 2011) collected data representative for real life Japanese asthmatics using a com-puter assisted telephone inter-view. The study included 400 adult asthmatics (27% males, mean age 46.4 years old), with mild inter-mittent asthma (65 %), mild per-sistent asthma (17%), moderate persistent asthma (8%) and severe persistent asthma (11%). In the last month thirty-four percent of adult asthmatics received inhaled cor-ticosteroids (ICS) or ICS and long acting β2-agonists (LABA) combi-nation (ICS/LABA). Only 41% of 304 asthmatics used regularly the drugs for 10 months or longer and 14% did not use any drug in the last year (Figure 1). The reasons for stopping the medication were:

ADHERENCE TO ASTHMA TREATMENT4

Ke y m e ssag e s

Adherence to asthma treatment

Ken Ohta National Hospital Organisation Tokyo

National Hospital, Japan

Hiroyuki Nagase Teikyo University

Tokyo, Japan

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disappearance of asthma symp-toms (61%), relief from the asthma attack (39%) and unexpectedly, doctor’s suggestion (17%). As a re-sult of poor adherence, 62% of the patients were symptomatic in the last month. Eighty-five percent of the asthmatics did not receive any information on the existence of guidelines for the management of asthma.

A cohort study evaluating 5563 new users of ICS and 297 new us-ers of ICS/LABA (age<35 years) in The Netherlands also showed poor adherence to maintenance

treatment with ICS regular use by less than 10% of patients and ICS/LABA use by less than 15%. Similar rates were observed when strati-fied for age (Figure 2). This study concluded that adherence to reg-ular treatment in asthma is influ-enced by patient factors, such as asthma severity, and treatment-re-lated factors, such as once-daily dosing frequency.

In the 2012 the updated Global Strategy for Asthma Management and Prevention (GINA) classified factors involved in poor adherence to treatment as drug factors (Table

1) and non-drug factors (Table 2). Most of the non-drug factors can be overcome by an improved doc-tor - patient communication. GINA 2012 recommends for the usual care level short questionnaires to identify poor adherence instead of prescription monitoring and pill counting. The approach is depend-ent on the level of trust subsidized in the doctor-patient relationship. An example question offered by GINA is “So that we may plan ther-apy, do you mind telling me how often you actually take medicine?”

Improving the reliability of clinical


Figure 1 Adherence to ICS or ICS/LABA in the AIRJ study. Data from adult asthmatics who had used ICS or ICS/LABA at least once in the past. Adherence was assessed by duration of use of ICS or ICS/LABA in the recent one year.

Figure 2 Overall adherence to ICS and fixed drug combinations in new users with asthma. (Reproduced from Breekveldt-Postma NS, Koerselman J, Erkens JA, et al. Treatment with inhaled corticosteroids in asthma is too often discontinued.

Pharmacoepidemiol Drug Saf 2008;17:411-22 with permission from John Wiley and Sons, Inc.)

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TABLE 1

Drug factors involved in poor adherence *

• Difficulties with inhaler devices

• Awkward regimens (e.g. four times daily or multiple drugs

• Side effects

• Cost of medication

• Distant pharmacies

* Reproduced from the Global Strategy for Asthma Management and Prevention 2012 with permission of Global Initiative for Asthma (GINA).

TABLE 2

Non-drug factors involved in poor adherence *

• Misunderstanding or lack of instruction

• Fears about side-effects

• Dissatisfaction with health care professionals

• Unexpressed/undiscussed fears or concerns

• Inappropriate expectations

• Poor supervision, training, or follow-up

• Anger about condition or its treatment

• Underestimation of severity

• Cultural issues

• Stigmatization

• Forgetfulness or complacency

• Attitudes toward ill health

• Religious issues

* Reproduced from the Global Strategy for Asthma Management and Prevention 2012 with permission of Global Initiative for Asthma (GINA).

judgment implies a correct evalu-ation of the patient’s expectations from the drug and for the course of the disease (the necessity-concern construct) and of the potential im-pediments (financial, psycho-so-cial and cultural, such a steroid phobia). Clear instructions provid-ed by health professionals, social

Figure 3 Adherence patterns in asthmatic children.

support and discussion groups for a better understanding of the dis-ease and active measures of main-taining contact with patients are recommended.

KEY REFERENCES1. Horne R. Concordance and med-

icines management in the res-piratory arena. London: Hayward Medical Publications, 2003.

2. Adachi M, Ohta K, Tohda Y, Mori-kawa A, Nishina S. Asthma In-sights and Reality in Japan: AIRJ 2011. Allergology & Immunology 2012; 19:1562-1570.

3. Breekveldt-Postma NS, Ko-erselman J, Erkens JA, van der Mo-

len T, Lammers JW, Herings RM, et al. Treatment with inhaled corti-costeroids in asthma is too often discontinued. Pharmacoepidemiol Drug Saf 2008;17:411-422.

4. From the Global Strategy for Asthma Management and Preven-tion. Global Initiative for Asthma (GINA), 2012. Available from: www.ginasthma.org.

5. Haynes RB, Wang E, Gomes MM. A critical review of interventions to improve compliance with pre-scribed medications. Patient Educ and Couns. 1987;10:155-166.

6. Horne R. Compliance, adher-ence, and concordance: implica-tions for asthma treatment. Chest 2006;130:65S-72S.

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ma • Asthma rates and severity are rising globally, but dispropor-

tionately impact low socio-economic status (SES), minority, and urban populations

• Social stratification can significantly influence asthma outcomes through mediation of exposure to risk and protective factors

• Low-SES individuals are more likely to be exposed to environ-mental pollutants, indoor allergens, and other respiratory irritants that adversely affect asthma

• Low-SES individuals are also more likely to be exposed to psychosocial stressors such as community and domestic violence as well as poor housing

• Efforts to eliminate asthma disparities must address both environmental and psychosocial determinants of asthma, which will require reducing exposure, especially among low-SES groups

Asthma is a complex developmen-tal condition, the impact of which is highly socially patterned. Though asthma prevalence and morbidi-ty are on the rise globally, this in-crease is not uniformly distributed, with a disproportionate asthma burden falling on low socio-eco-nomic status (SES) and/or minority populations residing in urban are-as. Moreover, in the United States this burden has been found to be highly clustered within urban com-munities particularly marked by social adversity and deprivation, most notably those containing a high percentage of African-Amer-ican or Puerto Rican residents. This community-level inequality is mirrored by worldwide trends in asthma prevalence and severity published in the most recent Glob-al Asthma Report of the Interna-tional Study of Asthma and Aller-gies in Childhood (ISAAC). Time trends analyses contained within this 2011 report found that rising global prevalence estimates are being driven primarily by rapid in-creases in low and middle-income countries with large populations, while prevalence in many high-in-come countries reached a plateau or even began to decrease. Similar-ly, phase three of ISAAC found that asthma is more severe in low and

middle-income countries.

A social determinants of health approach acknowledges that so-cial stratification can significant-ly influence health outcomes through mediation of exposure to risk and protective factors at both the household and communi-ty levels. For instance, individuals living in poverty are more likely to be exposed to environmental pollutants (e.g. particles related to the combustion of diesel and cooking fuels), indoor allergens (e.g. mold and dust containing mouse or cockroach excrement),

and other respiratory irritants (e.g. tobacco smoke). However, these differences in environmental ex-posures alone do not fully explain the significantly increased asthma risk found in certain socially dis-advantaged populations. Though the etiology of this excess asthma burden remains unclear, exposure to violent crime was recently impli-cated as an environmental factor impacting pediatric asthma preva-lence in a large urban cohort, with exposure to community violence conceptualized as a source of psy-chosocial stress. Indeed, commu-nity, family and individual-level

SOCIAL DETERMINANTS OF ASTHMA5

Ke y m e ssag e s

Social determinants of asthma

Ruchi S. Gupta Christopher M. Warren Northwestern University

Chicago, USA

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exposure to psychosocial stressors (Figure 1) increasingly character-ized as “social pollutants”, has been shown to predict some of this addi-tional variation in asthma risk. Be-yond exposure to community and domestic violence, these stressors can include food, housing, and fi-nancial insecurity as well as social marginalization. Conversely, there is evidence that community vital-ity/collective efficacy, increased maternal-child interaction, and ef-fective utilization of psychological coping strategies (e.g. “shift-and-persist”) may positively impact asthma outcomes at the communi-ty, family and individual levels.

Much as environmental pollutants like diesel exhaust enter the body and disrupt biological systems via pro-inflammatory processes, the “social pollutant” model of psycho-social stress hypothesizes that it also “gets under the skin” leading

to the dysregulation of inflamma-tory processes. In general, low-SES individuals are more likely to en-counter both psychosocial stress-ors and physical environmental toxins that may each independent-ly contribute to the increased asthma burden levied upon these populations (Figure 2). Moreover, given that these psychosocial and physical stressors often co-occur in disadvantaged environments and may influence common physio-logical pathways, it is possible that the aforementioned psychosocial stressors may potentiate an indi-vidual’s susceptibility to environ-mental exposures, thus giving rise to further asthma disparities.

Given the considerable evidence linking social inequality to popula-tion-level asthma disparities, it is clear that health equity cannot be achieved without taking concrete steps to address societal inequality

Figure 1 Ecological framework of the relation

between psychosocial stressors and asthma

morbidity. (Reproduced from Yonas MA, Lange NE, Celedón JC. Psychosocial

stress and asthma morbidity. Curr Opin Allergy Clin

Immunol. 2012;12:202-210.)

Figure 2 Asthma mural depicting psychological and environmental stressors. (From http://aceandson.com/blog/?p=948, accessed May 20, 2013)

Social determinants of asthma

more broadly. Efforts to eliminate asthma disparities must include direct acknowledgement of social determinants of health such as poverty, racism, lack of economic opportunity and community dep-rivation. Furthermore, structural and policy interventions must ad-dress these root causes of asthma disparities at the community and broader societal level, and accom-pany efforts to ensure effective disease self-management at the family and individual levels.

KEY REFERENCES1. Gold D, Wright R. Population dis-

parities in asthma. Annual Review of Public Health 2005;26:89-113.

2. Williams D, Sternthal M, Wright R. Social determinants: taking the social context of asthma seriously. Pediatrics 2009;123:S174-184.

3. Gupta R, Zhang X, Springston E, Sharp L, Curtis L, Shalowitz M, et al. The association between community crime and childhood asthma prevalence in Chica-go. Ann Allergy Asthma Immunol 2010;104:299-306.

4. Yonas MA, Lange NE, Celedón JC. Psychosocial stress and asthma morbidity. Curr Opin Allergy Clin Immunol 2012;12:202-210.

5. Wright R. Psychological stress: a social pollutant that may enhance environmental risk. Am J Respir Crit Care Med 2011;184:752-754.

Community-Level FactorsNegative: low socioeconomic status (SES), violence/violence exposure, community crime, poor housingPositive: collective efficacy

Maternal / Family-Level Factors

Negative: prenatal maternal stress, intimate partner violence (IPV), maternal stress, paternal stress, poor housing conditionsPositive: maternal-child interaction and activities

Individual-Level FactorsNegative: post-traumatic stress disorder, trauma, low SES, air pollution, genetic/epigenetic factorsPositive: stress management, problem solving and relaxation strategies, shift and persistent strategies, genetic/epigenetic factors

COMMUNITY LEVEL FAMILY LEVELINDIVIDUAL LEVEL

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or medical care in many areas of the world• The solution to the problem in developing countries will not be

achieved only by improving access to medication• National Health Ministries must consider asthma as a public

health priority• National programmes need to be implemented to improve

diagnosis, management, and reduce direct and indirect costs• Evidence from well-established national asthma management

programmes proves a substantial improvement of asthma burden

The International Study of Asthma and Allergies in Childhood (ISAAC) Phase 3 study has demonstrated that the prevalence of asthma in African and Latin American chil-dren, assessed by a self-reported questionnaire, is higher than the global average. In addition, chil-dren with asthma in low and mid-dle-income countries, have more severe symptoms than those in high-income settings, possibly due to lack of diagnosis, poor access to care, lack of affordability of thera-py, environmental irritants, genetic susceptibility to more severe dis-ease or a combination of these.

Despite access to appropriate healthcare resources, several stud-ies have demonstrated that asth-ma is often underdiagnosed and undertreated in many parts of the world.

The multinational Asthma Insights and Reality (AIR) surveys show the rate of exacerbation, including hos-pitalizations, emergency room vis-its and unscheduled visits to physi-cian office, are higher in Asia Pacific and Latin America compared to Eu-rope and USA. The same observa-tion was made for the indirect cost of asthma evaluated by the level of school and work absenticism.

Close to 50% of medical expendi-

tures for asthma are a consequence of exacerbations. There are only a few pharmacoeconomic studies in developing countries. In Latin America, unscheduled health care resource use was particularly high among patients with uncontrolled asthma. For both adults and chil-dren, scheduled health care costs were approximately 3-fold high-er in those with severe persistent symptoms than in those with mild intermittent symptoms. Regard-less of symptom severity, almost threequarters of expenditure was due to unscheduled health care.

One succesfull program (ProAR) was developed in 2003 in Salva-dor, Brazil, prioritising the control of severe asthma. By facilitating referrals from the public health

system and providing proper multidisciplinary, but simple, man-agement including education and medication for free, ProAR en-rolled >4,000 patients with severe asthma. The patients were offered regular follow-up and were re-ferred back to primary healthcare only when asthma control could be maintained without requirement of a combination therapy. This in-tervention was associated with a steep decline in health resource utilisation and remarkably reduced the rate of hospital admissions due to asthma by 74% in 3 yrs in the en-tire 2.8 million city habitants. Cost analysis demonstrated that this in-tervention was very cost-effective and provided a financial relief to the families and the government.

INEQUITIES AND ASTHMA6

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Hugo E. Neffen Children´s Hospital “Orlando Alassia”

Santa Fe, Argentina

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In many areas of the World, per-sons with asthma do not have ac-cess to basic asthma medications or medical care (Figure 1).

The solution to the problem in developing countries will not be

achieved only by improving access to medication; National Health Ministries must consider asthma as a public health priority, and na-tional programmes need to be im-plemented in order to improve di-

agnosis, management, and reduce direct and indirect related costs.

Evidence from the studies con-ducted in countries with well-es-tablished or developing national asthma management programmes suggests that establishment of an overall successful programme requires a logical progression through specific stages, starting with epidemiological evaluation and leading up to optimisation and maintenance therapy for individu-al patients (Figure 2). Each devel-opment stage is likely to present a multitude of local and national challenges and specific implemen-tation strategies, which will deter-mine the overall success level of the asthma management programme.

KEY REFERENCES1. Asher MI, Montefort S, Björkstén

B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunc-tivitis, and eczema in childhood: ISAAC Phases One and Three re-peat multicountry cross-sectional surveys. Lancet 2006;368:733-743.

2. Sánchez-Borges M, Capriles-Hu-lett A, Caballero-Fonseca F. Asth-ma care in resource-poor settings. World Allergy Organ J 2011;4:68-72.

3. Rabe KF, Adachi M, Lai CK, Sori-ano JB, Vermeire PA, Weiss KB, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and re-ality surveys. J Allergy Clin Immunol 2004;114:40-47.

4. Neffen H, Gonzalez SN, Fritscher CC, Dovali C, Williams AE. The burden of unscheduled health care for asthma in Latin Ameri-ca. J Investig Allergol Clin Immunol 2010;20:596-601.

5. Souza-Machado C, Souza-Macha-do A, Franco R, Ponte EV, Barreto ML, Rodrigues LC, et al. Rapid re-duction in hospitalisations after an intervention to manage severe asthma. Eur Respir J 2010;35:515-521.

Figure 1 World Map of the Proportion of the Population with Access to Essential Drugs. (Reproduced from Masoli M, Fabian D, Holt S, et al. Global Burden of

Asthma. 2004, Global Initiative for Asthma (GINA).)

Figure 2 Essential steps for a successful asthma management program. (Reprinted with permission of the International Union Against Tuberculosis and Lung

Disease. Copyright © The Union. Lalloo UG, Walters RD, Adachi M, et al. Asthma programmes in diverse regions of the world: challenges, successes and lessons learnt.

Int J Tuberc Lung Dis 2011;15:1574-1587.)

Inequities and asthma

Access to best therapy

(ICS/ICS-LABA)

Optimisation and maintenance

Access to care(Public or private)

Burden of disease(Patient / societal)

Epidemiology(Prevalence of disease at national/regional/ethnic level

Political endorsement and commitment of all stakeholders(Government / Healthcare Organisations/ Professionals /

Pharmaceutical Industry)

LEVE

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Section D

PREVENTION AND CONTROL

OF ASTHMA

* Primary and secondary prevention of asthma* Allergen immunotherapy in asthma* Asthma control* Best buys for asthma prevention and control* Evidence for asthma control – zero tolerance to asthma

with the Finnish programmes * The need for integrated and complimentary strategies in

the political agenda* Policies and strategies to facilitate access to asthma

diagnosis and treatment* Policies and strategies to reduce risk factors for asthma* Tobacco control and asthma* Implementation of a healthy life style and asthma* Individual interventions for asthma prevention and

control

* The role of Primary Care in the prevention and control of asthma

* Role of patient organisations in the control and prevention of asthma

* Social mobilization for prevention and control of asthma * Asthma in resource constrained settings* Dealing with the implementation gap for asthma

prevention and control* Generating resources for prevention and control of

asthma* Asthma prevention and control: Why it should not be

ignored any longer?* Vision, roadmap and a land-marking event

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• Avoid smoking, including prenatal and second hand exposure• Repair possible housing moisture damage• Avoid traffic air pollution, if possible• Participate in regular physical activity• Include fruits and fish in food• Pet avoidance reduce symptoms and exacerbations in patients

with asthma, but does not prevent asthma development• Breast milk is recommended, but does not protect against asthma

Lifetime risk of asthma approxi-mates 35%, most often starting early in life. Preventive measures reducing asthma prevalence and burden will have significant impact on healthy ageing, general popula-tion health and societal costs.

Primary prevention of asthma involves preventing disease de-velopment, whereas secondary prevention refers to preventing new asthma in subjects who have expressed other atopic diseas-es like atopic eczema or allergic rhinitis (Table 1, Figure 1). Pre-vention strategies should be well documented before implementa-tion, ideally through randomised controlled intervention studies. Prospective observation studies may suggest potential benefits of the measures. Primary prevention should not be harmful, and should be applicable to the general popu-lation, since we are currently not able to predict asthma in early childhood. Recent studies have cast doubt on some previous pri-mary prevention advice, possibly due to a change in causative fac-tors for asthma development from “old” high-risk patients to the many “new” asthma cases of later years due to a change in our modern en-vironment.

PREVENTABLE RISK FACTORSTable 2 presents preventable risk factors for allergy and asthma.

Prenatal and second-hand tobac-co smoke exposure increases risk of asthma and wheezing through-out childhood. Prenatal smoke ex-posure reduces lung function in the neonate. Low infant lung function tracks through childhood to adult-hood. Smoke exposure is an im-portant risk factor for severe adult lung disease, as for childhood asth-ma. Smoke induces methylation of genes protecting against smoke exposure. Intervention reduces morbidity as shown by the effect of smoke legislation on childhood asthma hospitalization. Reduction of smoke exposure represents impor-tant primary and secondary asthma prevention.

Moisture damage is a consistent finding in observational birth co-hort and cross-sectional studies of housing conditions and childhood asthma. Housing conditions should be improved when moisture damage is present.

Air pollution, especially traffic and diesel vehicle pollution, increases risk of asthma development and asthma symptoms in children and reduces lung function, as shown in observational studies. Living close to heavy trafficked highways increases asthma risk and reduces lung growth through childhood. Re-ducing traffic pollution, particularly from diesel exhaust, is a primary asth-ma preventive measure that should be implemented by politicians and community planners.

Kai-Håkon Carlsen Karin C. Lødrup Carlsen University of Oslo

Norway

PRIMARY AND SECONDARY PREVENTION OF ASTHMA1

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TABLE 1

Definition of primary, secondary and tertiary prevention

Prevention - Level Definition

Primary Prevent occurrence of disease

SecondaryPrevent development of disease after first signs of disease have presented or predisposing factors are present

TertiaryPrevent disease symptoms and progression including treatment, attempting to minimize the long-term effects of the disease.

Respiratory virus infections, as respiratory syncytial virus (RSV) bronchiolitis, increase the asthma risk. Rhinovirus infections induce acute asthma in asthma patients. Presently only humanised anti-body against RSV virus reduces the risk of bronchiolitis, but the inter-vention is reserved for high-risk children. One observational study

shows that RSV antibody given for the prevention of acute bronchioli-tis reduces the risk of later asthma. RSV vaccination represents a poten-tial primary preventive measure.

Early allergen exposure has been anticipated to increase the risk of allergic sensitization and asthma. Consequently, advising against pet keeping has been widely adopt-

ed. This advice was recently chal-lenged, with a European study including 20000 children from sev-eral European birth cohort studies reporting no significant associa-tion between early pet keeping and asthma at school age. On the other hand, in case of asthma with aller-gic pet sensitization, pet avoidance will reduce symptoms. Mite sensi-

TABLE 2

What advice can we give at present time for primary and secondary asthma prevention?

Prevention Measure - Advice Study designs

Primary prevention

Avoid primary and second hand smoke exposureObservational and intervention studies

Moisture damage should be repaired.Observational birth cohort and cross-sectional studies

Avoid traffic air pollution. Do not live close to highways. Kindergartens should not be positioned closed to highways.

Observational studies

Humanised antibody against RS-virus reduces the risk of bronchiolitis which may reduce the risk of later asthma development

One interventional study

Early pet keeping. No advice. Observational studies

Recommend regular intake of fish, Ω-3 fatty acids and antioxidant vitamins


Recommend physical activity and trainingMeta-analysis. Longitudinal and cross-sectional observational studies

Secondary prevention

Avoid primary and secondary smoke exposureObservational and interventional studies

Avoid traffic air pollution. Do not live close to highways. Kindergartens should not be positioned closed to highways.


Pet avoidance will reduce symptoms in asthma pa-tients with allergic sensitization to pets.


Recommend physical activity and training (reduces airways inflammation and improves fitness and self perception).

Observational and interventional studies

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Figure 1 Primary and secondary asthma prevention.

tization increases asthma risk, but presently there is no convincing primary preventive effect on asth-ma by mite reduction measures. Presently no advice should be given with regard to pet keeping for primary prevention of asthma.

FACTORS PROTECTING AGAINST ASTHMA DEVELOPMENTSeveral observational studies sug-gest that inclusion of certain foods in diet may protect against asthma development. This includes regular fish, Ω-3 fatty acids and fruit intake with respect to asthma and lung function development in healthy children.

Breast milk up to 6 months of age has been recommended to prevent asthma and allergy development. Several recent studies question this, and present evidence does not support that breast milk protect against asthma and allergy devel-

opment. However, there are sever-al other reasons for recommending breast milk feeding, both nutrition-al and protection against infection.

Physical activity is recommended to improve general health. A re-cent meta-analysis of studies in all ages found physical activity to pro-tect against asthma development. Physical training was reported to reduce airways inflammation and improve fitness in asthma. How-ever, no effect upon lung function and bronchial responsiveness was found.

Allergen immunotherapy as sec-ondary prevention has been stat-ed to prevent asthma in children with allergic rhinitis. However, with only one interventional mul-ticentre study the evidence for this is presently too weak.

KEY REFERENCES1. Håland G, Carlsen KC, Sandvik L,

Devulapalli CS, Munthe-Kaas MC,

Pettersen M, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006;355:1682-1689.

2. Svanes C, Sunyer J, Plana E, Dhar-mage S, Heinrich J, Jarvis D, et al. Early life origins of chronic ob-structive pulmonary disease. Tho-rax 2010;65:14-20.

3. Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Pre-natal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 2009;180:462-467.

4. Lødrup Carlsen KC, Roll S, Carls-en KH, Mowinckel P, Wijga AH, Brunekreef B, et al. Does pet own-ership in infancy lead to asthma or allergy at school age? Pooled anal-ysis of individual participant data from 11 European birth cohorts. PLoS One 2012;7:e43214.

5. Eijkemans M, Mommers M, Draa-isma JM, Thijs C, Prins MH. Phys-ical activity and asthma: a system-atic review and meta-analysis. PLoS One 2012;7:e50775.

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• Allergen immunotherapy is the only effective etiological treatment for respiratory allergy, which has the potential to change the course of the allergic disease

• The efficacy and safety of immunotherapy in allergic asthma have been demonstrated in controlled clinical trials

• Subcutaneous immunotherapy with some aero-allergens and good quality extracts has been shown to reduce significantly allergen specific bronchial hyperreactivity

• Sublingual immunotherapy is a good alternative for treating allergic asthma, but more evidence is needed to support its efficacy and safety

Allergen immunotherapy (AIT) is the only effective etiological treatment for respiratory allergy, which has the potential to change the course of the disease, thus improving quality of life, and re-ducing long-term costs and bur-den of allergies. Its immunological mechanisms of action have been demonstrated as induction of al-lergen-specific immune tolerance by regulatory T cells, specific an-tibody isotype change from IgE to IgG4 and decrease in the activity and mediators of eosinophils, mast cells and basophils.

However, unlike for allergic rhini-tis, the role of immunotherapy in allergic asthma is still a matter of debate. Many controlled clinical trials have shown the efficacy and safety of AIT in allergic asthma. Some published meta-analyses (Ta-ble 1), have confirmed these find-ings, despite some methodological and clinical weaknesses. In a most recent meta-analysis on subcuta-neous immunotherapy (SCIT) for allergic asthma, the authors have shown an overall significant reduc-tion in asthma symptoms and med-ication use. It would have been nec-essary to treat three patients (95% CI 3 to 5) with SCIT to avoid one deterioration in asthma symptoms,

and to treat four patients (95% CI 3 to 6) with AIT to avoid one requir-ing increased medication.

As for children, individual pediatric studies have shown moderate effi-cacy of SCIT in seasonal and peren-nial asthma and significant reduc-tion in inhaled corticosteroid (ICS) doses in mite-induced asthma. This is of particular importance as aller-gic asthma is frequently associated with allergic rhinitis with the con-sequent need of simultaneous na-sal steroid therapy. Furthermore, there is a concern of the possible adverse effects of long-term treat-ment with ICS in children. No chil-dren’s sub-analysis was performed in the Abramson’s Cochrane me-

ta-analysis on SCIT and there is no clear consensus regarding the use of SLIT in asthmatic allergic chil-dren.

SCIT significantly reduced allergen specific bronchial hyperreactivity (Table 2), which was evaluated in the majority of the studies after one year of treatment. This is an important finding from a clinical point of view as the measurement of this parameter is the only accu-rate method of assessing the risk of an acute episode of asthma due to a sudden and increased level of an aeroallergen exposure, as in the case of mould allergic patients. Moreover SCIT is able to decrease not only early, but also late asth-

M. Beatrice Bilò Ospedali Riuniti di Ancona

Italy

Moisés Calderón Imperial College

London, UK

Victòria Cardona Hospital Vall d’Hebron

Barcelona, Spain

ALLERGEN IMMUNOTHERAPY IN ASTHMA2

Ke y m e ssag e s

Allergen immunotherapy in asthma

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matic responses following allergen bronchial challenge, the presence of which is considered an experi-mental model resembling chronic bronchial allergic inflammation, thus confirming the anti-inflamma-tory effect of the AIT in the lung.

Evidences do exist for the effica-cy of sublingual immunotherapy

(SLIT), but SLIT meta-analyses are mostly questioned due to large methodological heterogeneity and inconsistencies (Table 1). SLIT is generally considered to have a bet-ter safety profile than SCIT both in children and adults. The risk of a systemic reaction to SCIT is great-er in subjects with uncontrolled

asthma and with accelerated dos-ing schedules. Systematic reviews have shown that SCIT is a safe therapeutic intervention when it is prescribed to well-selected pa-tients, even in asthmatic children, and given in a specialist clinic with adequate facilities and by trained medical personnel.


TABLE 1

Meta-analysis of studies of AIT in asthma

Disease AuthorStudies

(n)Population

Participants Effect Size SMD (95% CI)

Hetero-geneity

I2Active (n) Placebo (n)

Sym

pto

m S

core

s SCIT

Asthma Abramson MJ 2010 34 Adults and children 727 557 -0.59 (-0.83,-0.35) 73%

SLIT

Asthma Calamita Z 2006 9 Adults and children 150 153 -0.38 (-0.79, 0.03) 64%

Asthma Penagos M 2008 9 Children 232 209 -1.14 (-2.10, -0.18) 94%

Med

icat

ion

Sco

res SCIT

Asthma Abramson MJ 2010 20 Adults and children 485 384 -0.53 (-0.80, -0.27) 67%

SLIT

Asthma Calamita Z 2006 6 Adults and children 132 122 -0.91 (-1.94, 0.12) 92%

Asthma Penagos M 2008 7 Children 192 174 -1.63 (-2.83, -0.44) 95%

Effect size (SMD - Standardized mean difference): poor <-0.20; medium = -0.50; high >-0.80Heterogeneity (I2) = 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity

TABLE 2

Injection allergen immunotherapy for asthma: summary of allergen-specific bronchial hyperreactivity indices *

Allergen-specific BHR index Studies (participants) SMD (95% CI)

Log PD20

mite 6 (148) -0.98 (-1.39 to -0.58)

Log PD20

pollen 5 (202) -0.55 (-0.84 to -0.27)

Log PD20

animal dander 6 (153) -0.61 (-0.95 to -0.27)

Log PD20

/PC100

other allergens 2 (61) -0.18 (-0.70 to 0.33)

Total 19 (564) -0.61 (-0.79 to -0.43)

* Reproduced from Cox L, Calderón M, Pfaar O. Subcutaneous allergen immunotherapy for allergic disease: examining efficacy, safety and cost-effectiveness of current and novel formulations. Immunotherapy. 2012;4:601-16 with permission of Future Medicine Ltd.BHR: Bronchial hyperreactivity; PC100: Concentration required to produce a 100% increase in lung resistance; PD20: Provocative dose required to produce a 20% fall in forced expiratory volume in 1s; SMD: Standardized mean difference.

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UNMET NEEDS• The main need is to perform sep-

arate clinical studies in adults and in children with allergic asthma, following standardized protocols, as recommended by international guidelines.

• Studies of AIT in allergic asthma should also focus more on the long term effect of the treat-ment (as well as on a long-term steroid-sparing effect) rather than considering only the imme-diate efficacy on allergic symp-toms.

• Specific asthma features, like bronchial hyperreactivity, asth-ma control and exacerbations should be included among the study primary or secondary out-comes.

• Assessing the safety of SLIT in moderate to severe asthmatics is still an unmet need.

• The unmet needs of AIT have to be evaluated in an integrat-ed multinational academic, re-search, industry and regulatory agencies effort in Europe.

In the recent European Declara-tion on Immunotherapy EAACI calls upon Europe’s policy-makers to coordinate actions and improve individual and public health in al-lergy by promoting immunother-apy awareness, updating national healthcare policies to support al-lergen immunotherapy and prior-itising funding for immunotherapy research (Figure 1).

KEY REFERENCES1. Calamita Z, Saconato H, Pelá AB,

Atallah AN. Efficacy of sublingual immunotherapy in asthma: sys-tematic review of randomized- clinical trials using the Cochrane Collaboration method. Allergy 2006;61:1162-1172.

2. Penagos M, Passalacqua G, Com-palati E, Baena-Cagnani CE, Oroz-co S, Pedroza A, et al. Metaanal-ysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric pa-tients, 3 to 18 years of age. Chest 2008;133:599-609.

3. Abramson MJ, Puy RM, Weiner JM. Injection allergen immuno-therapy for asthma. Cochrane Data-base Syst Rev 2010(8):CD001186.

4. Calderon MA, Gerth van Wijk R, Eichler I, Matricardi PM, Varga EM, Kopp MV, et al. Perspectives on allergen-specific immunother-apy in childhood: an EAACI posi-tion statement. Pediatr Allergy Im-munol 2012;23:300-306.

5. Zielen S, Kardos P, Madonini E. Steroid sparing effects with al-lergen-specific immunotherapy in children with asthma: a rand-omized controlled trial. J Allergy Clin Immunol 2010:126:942–949.

6. Jutel M, Akdis CA. Immunologi-cal mechanisms of allergen-spe-cific immunotherapy. Allergy 2011;66:725-732.

Figure 1 EAACI declaration on immunotherapy. (http://www.eaaci.org/resources/immunotherapy-declaration.html, accessed May 20, 2013)

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a • Optimal asthma control is the goal of asthma management• Optimal asthma control consists of current (day to day) control

and reduced future risk• Asthma control and asthma severity are not synonymous• Asthma control can be achieved in the majority of patients• The most common reason for poor control is lack of adherence to

medications• There are several validated questionnaires to measure asthma

control in research studies

National and international guide-lines for asthma management have identified that the primary goal of management is to achieve asthma control. Asthma control consists of two domains. These are optimizing current (day-to-day) control, de-fined as the minimization of both daytime and night time symptoms, no limitation of activity, minimal rescue bronchodilator use and no airway narrowing; and minimizing future risk defined by long term de-cline in lung function, severe asth-ma exacerbations and unwanted effects from medications (Figure 1). The two domains which define asthma control are not independ-ent. The more poorly controlled day-to-day asthma is, the greater the risk of a severe asthma exacer-bation.

In the past, physicians were often confused by the terms ‘‘asthma control” and “asthma severity”. It was perceived that well-controlled asthma was synonymous with mild asthma and poorly controlled asth-ma was synonymous with severe asthma. This perception is incor-rect. Severity is the intensity of the underlying disease process before treatment, and control is the ad-equacy of the response to treat-ment. Patients with severe asthma,

if treated appropriately can be well controlled and patients with mild asthma, if they fail to follow treat-ment guidelines, will have inade-quately controlled asthma, which may be perceived as severe (Figure 2). The goals of asthma manage-ment are the same for all degrees of asthma severity. Although patients with severe asthma will often be more difficult to control with an intervention, effective treatment can potentially fully control pa-tients with severe asthma.

An American Thoracic Society and the European Respiratory Society joint Working Group have made recommendations about the im-portant components of asthma control and their measurement. In addition, there are a range of ques-tionnaires and diaries that have

been developed to measure cur-rent asthma control and each one of which has strengths and weak-nesses. Among the most common-ly used are the Asthma Control Questionnaire (ACQ), the Asthma Control Test (ACT), and the Asth-ma Therapy Assessment Question-naire (ATAQ).

Despite the availability of effec-tive and safe medications to treat asthma, the most important of which are inhaled corticosteroids, either alone or in combination with long-acting inhaled β2-agonists, many patients remain poorly con-trolled. The most important reason for this is poor adherence to treat-ment regimes. When patients are taking their asthma medications, many can achieve well controlled asthma; in some instances, how-

Paul M. O’Byrne McMaster University

Hamilton, Canada

ASTHMA CONTROL3

Ke y m e ssag e s

Asthma control

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Figure 1 Overall asthma control. (Reprinted from J Allergy Clin Immunol, 125/3, Bateman ED, Reddel HK, Eriksson G, et al, Overall asthma control: the relationship

between current control and future risk, 600-608, Copyright 2010, with permission from Elsevier.)

Asthma control

ever, asthma may be only partly controlled and a decision needs to be made by the patients and their managing health care professional whether to increase the treatment, or to accept partly controlled asth-ma. However, all guidelines indi-cate that if asthma is uncontrolled, treatment options should be care-fully evaluated and additional treatment added.

There is a subset of asthmatic pa-tients who, despite treatment with

optimal doses of asthma medica-tions, have uncontrolled asthma and are at risk for severe asthma exacerbations. These are consid-ered severe refractory asthmatics, and are 5-10% of the asthma popu-lation and are the group of patients where phenotyping with relation to their atopic status, and the type of airway inflammation present, may provide additional useful in-formation with regards to newer treatment options.

Figure 2 Percentage of patients with controlled/partly controlled or uncontrolled asthma (GINA classification) according to asthma severity

(Reprinted from Ann Allergy Asthma Immunol, 107/6, Korn S, Both J, Jung M, et al. Prospective evaluation of current asthma control using ACQ and ACT compared with

GINA criteria, 474-479, Copyright 2011, with permission from Elsevier.)

100

80

60

40

20

0intermittent mild persistent moderate

persistentsevere

persistent

% of patients controlled / partly controlled uncontrolled

Overall Asthma Control

Current Control

Symptoms

Activity

Reliever use

Lung function

defined by

Future risk

Instability/ worsening

Lung function loss

Exacerbations

Medication adverse effects

defined by

achieving reducing

KEY REFERENCES1. Bateman ED, Reddel HK, Eriksson

G, Peterson S, Ostlund O, Sears MR, et al. Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol 2010;125:600-608.

2. Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB et al. A new perspective on concepts of asthma severity and control. Eur Respir J 2008;32:545-554.

3. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Develop-ment and validation of a question-naire to measure asthma control. Eur Respir J 1999;14:902-907.

4. Nathan RA, Sorkness CA, Kosin-ski M, Schatz M, Li JT, Marcus P et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Im-munol 2004;113:59-65.

5. Vollmer WM, Markson LE, O’Con-nor E, Sanocki LL, Fitterman L, Berger M, et al. Association of asthma control with health care utilization and quality of life. Am J Respir Crit Care Med 1999;160:1647-1652.

6. Demoly P, Annunziata K, Gubba E, Adamek L. Repeated cross-sec-tional survey of patient-report-ed asthma control in Europe in the past 5 years. Eur Respir Rev 2012;21:66-74.

7. Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, con-trol, and exacerbations: document presented for the World Health Organization Consultation on Se-vere Asthma. J Allergy Clin Immu-nol 2010;126:926-938.

8. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official Ameri-can Thoracic Society/European Respiratory Society statement: asthma control and exacerba-tions: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-99.

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a • A step-wise asthma management plan providing best-buy measures for asthma prevention and control is urgently needed

• Asthma should be recognised as a novel major public health problem

• Cost-efficient use of available resources, promotion of effective asthma management approaches and investment in innovative models and in asthma research are important steps forward

• Improving the distribution of resources between and within countries increases the accessibility to asthma diagnosis and to essential drugs

• Active involvement of all stakeholders is necessary to plan efficient management programs for asthma

With the projected increase in the proportion of the world’s popu-lation that is urban in 2025, there may be an additional 100 million persons with asthma adding to the existing world asthma population of 300 million individuals. In addi-tion, asthma morbidity and mortal-ity account for 1% of all disability adjusted life years (DALYs), equiv-alent to 16 million DALYs lost per year worldwide. A step-wise asth-ma management plan providing cost-efficient measures for asthma prevention and control is urgently needed (Figure 1).

Identify and address barriers which limit the efficiency of in-terventions aiming to prevent and control asthma. Many economic and political factors impact the ef-ficiency of asthma prevention and control strategies. Examples in-clude poverty, poor education and infrastructure, low public health priority and the lack of good world-wide valid data on morbidity and mortality from asthma.

Position asthma as an important cause of morbidity, economic cost, and mortality worldwide. The bur-den of asthma around the world is of sufficient magnitude to warrant its recognition as a priority disor-der in government health strate-

gies. The low public health priority of asthma due to the importance of other illnesses and to insufficient awareness of the general public and policy makers negatively im-pacts efficient funding and imple-mentation of asthma management plans.

Well-controlled epidemiological description and surveillance of asthma. National, regional and in-ternational asthma registries are urgently needed to continuously monitor the prevalence, morbidity and mortality of asthma at a global scale.

Cost-efficient use of available resources. Until asthma is rec-

ognised as a novel major public health problem and pharmacolog-ical measures become available to reduce the prevalence of asthma, resources need to be prioritised:

• to address asthma preventable risk factors, such as air pollution or tobacco smoke

• to improve the care of disadvan-taged groups with high morbid-ity

• to ensure that cost-effective management approaches which have been proven to reduce morbidity and mortality are available to as many persons as possible with asthma world-

Ioana Agache Transilvania University of Brasov

Romania

BEST BUYS FOR ASTHMA PREVENTION AND CONTROL4

Ke y m e ssag e s

Best buys for asthma prevention and control

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wide. Even if asthma control is not achieved, improvements in quality of life can still be ob-tained with appropriate treat-ment, thus lessening the asthma associated disability

• to support asthma research which should provide effective prevention, accurate and rapid diagnosis and a curative treat-ment of asthma

Improve accessibility to asthma diagnosis and to essential drugs in low- and middle-income coun-tries and for hard-to-reach pop-ulations. Most of the lifestyle-re-lated risk factors for asthma (poor hygiene or diet, obesity and psy-chosocial stress) are prevalent among the poor. In many areas of the world asthma sufferers do not have access to diagnosis or to basic asthma medications. Improving the distribution of resources between and within countries could enable better health care to be provided.

The “Yes We Can Urban Asthma Partnership” reaches out to high-risk children from underserved ur-ban areas in different settings: ur-gent visits, the hospital, a specialty

asthma clinic, and through an ex-panded community health worker programme. Significant increases in controller medications and ac-tion plans use and decrease in asth-ma symptoms were demonstrated. Additional changes occurred with-in the local system of asthma care to support ongoing efforts to im-prove asthma management.

The La Red intervention in the se-lected Puerto Rican communities experiencing a disproportionately high level of asthma burden com-bined the key components from the “Yes We Can” and the “Inner-City Asthma Study” interventions. The program significantly reduced asthma symptoms, asthma-related hospitalizations and emergency department use, and their associ-ated high costs.

Control the preventable environ-mental factors by using stand-ardised decision support tools. Decision support tools (DSTs) are used at various levels and by vari-ous stakeholders. A recent survey showed that DSTs address only one pollution source or environ-mental stressor, are only applied to

one chronic disease or one decision making area and are used only by national authority and/or munici-pality/urban level administration or only by environmental profes-sionals and researchers. There is a need to develop standardised DSTs covering an increasing number of pollution sources, environmental stressors and health end points.

Adapt international asthma guidelines to low- and middle-in-come countries and use realistic dissemination and implementa-tion strategies. Guidelines used to prevent and control asthma should be practical and realistic in terms of differences across cultures and health care systems and between high- and low and middle-income countries. Crowd-sourcing pro-vides an additional opportunity to increase the sustainability of the guidelines.

Promote cost-effective asthma management approaches and in-vest in innovative models. The Finnish experience proved that asthma prevention and control is achievable in a cost-efficient way.

Telemanagement of asthma in-

Figure 1 Asthma “best buys” management plan.

Advocacy from all the stakeholders

Asthma is recognised as a major health problem

Evaluate barriers to an efficient asthma management plan

Epidemiological surveillance (registries)

Practical and realistic guidelines

Special focus on “costly” disease (severe asthma, exacerbations)

Implement efficient programs and new models

Smart investment in asthma research

Increased access to diagnosis and treatment

Address preventable risk factors

Cost-effective use of resources

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cludes key components of asthma management, and is tailored to the individual patient needs. The approach is effective in improving quality of life and clinical outcomes, especially in adult patients with moderate to severe asthma. More research is needed on the long-term effectiveness and cost-effec-tiveness under real-world condi-tions.

The Healthy Living Pharmacy or the Chronic Care Model are new concepts designed to meet public health needs through community pharmacy, tailored to local require-ments for tackling health inequali-ties, or through multi-component remodelling of chronic disease ser-vices. Their applicability to asthma care was recently demonstrated.

Smart investment in asthma re-search. The “asthma epidemic” cannot be fully explained by the current knowledge of the causa-tion of asthma. In addition, very few intervention strategies to pre-vent and control asthma were fully successful.

Key priority areas in the field of asthma research are:

• unveiling the risk factors and mechanisms that cause asthma, including detailed phenotyping/endotyping

• novel biotechnological innova-tions and patient-oriented diag-nostic and treatment protocols

• well designed intervention strat-egies for asthma prevention and control, fully applicable in low and middle-income countries

Special focus on difficult-to-man-age and costly severe disease forms and/or exacerbations of asthma. Severe asthma consumes ~50% of the global asthma budget. A key challenge is to recognize and

treat factors that make asthma difficult to manage and to predict differences in response between groups of patients. A multidisci-plinary approach within specialist centers with experience and wider access to national and internation-al severe asthma networks was suggested.

Patients at risk of severe exacerba-tions contribute disproportionally to asthma mortality, morbidity and costs. Using asthma risk registers in primary care reduced hospital-isations and increased prescrip-tions of preventative therapies without increasing costs. Moni-toring induced sputum eosinophil cell counts is helpful in preventing exacerbations in some patients with severe asthma. Future devel-opments include better biomark-ers to predict exacerbations or the cause of exacerbations, augmenta-tion of the immunological response to viruses, the use of telemonitor-ing in patients with severe asthma and the development of improved therapies targeted at reducing ex-acerbations.

Involve all stakeholders. Active involvement of all stakeholders, including asthma educators, the primary care network, patient or-ganizations and policy makers are necessary to plan efficient man-agement programs for asthma.

Decisions by policy makers that are granting access to asthma diagno-sis and treatment are summoning action from patients, physicians, and their organizations. One of the strongest advocacy to date is from patient organizations, which strive to educate stakeholders on key is-sues that determine patient access to appropriate asthma diagnosis management. Advocacy by physi-cians at the local level is needed, as are national and international ef-

forts by organizations such as the European Academy of Allergy and Clinical Immunology.

KEY REFERENCES1. Mannino D. Chronic obstruc-

tive pulmonary disease in 2025: where are we headed? Eur Respir J 2005;26:189.

2. Bateman ED, Frith LF, Braunstein GL. Achieving guideline-based asth-ma control: does the patient bene-fit? Eur Respir J 2002;20:588-595.

3. Cooper PJ, Rodrigues LC, Barreto ML. Influence of poverty and in-fection on asthma in Latin Amer-ica. Curr Opin Allergy Clin Immunol 2012;12:171-178.

4. Thyne SM, Rising JP, Legion V, Love MB. The Yes We Can Urban Asth-ma Partnership: a medical/social model for childhood asthma man-agement. J Asthma 2006;43:667-673.

5. Lara M, Ramos-Valencia G, González-Gavillán JA, López-Mal-pica F, Morales-Reyes B, Marín H, et al. Reducing quality-of-care dis-parities in childhood asthma: La Red de Asma Infantil intervention in San Juan, Puerto Rico. Pediatrics 2013;131:S26-37.

6. Van Gaalen JL, Hashimoto S, Sont JK. Telemanagement in asthma: an innovative and effective ap-proach. Curr Opin Allergy Clin Im-munol 2012;12:235-240.

7. Brown D, Portlock J, Rutter P. Review of services provided by pharmacies that promote healthy living. Int J Clin Pharm 2012;34:399-409.

8. Fortin M, Chouinard MC, Bouhali T, Dubois MF, Gagnon C, Bélanger M. Evaluating the integration of chronic disease prevention and management services into prima-ry health care. BMC Health Serv Res 2013;13:132.

9. Papadopoulos NG, Agache I, Bavbek S, Bilo BM, Braido F, Car-dona V, et al. Research needs in al-lergy: an EAACI position paper, in collaboration with EFA. Clin Transl Allergy 2012;2:21.


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• Asthma is a public health problem. A community problem needs community solutions

• Most of asthma suffering is unnecessary. Every asthma death is an accident and potentially avoidable

• Asthma is a quite treatable disease, but much too often the diagnosis is severely delayed causing poor disease control

• To take asthma into control, “hit early and hit hard”. Keep up the control with individualized maintenance treatment and follow-up

• National and local action plans with defined goals, tools and outcome measurements are effective and reduce asthma burden with relatively simple means

• Networking of specialists, family physicians, nurses and pharmacists is the key to implement the best practices in health care

• Guided self-management is the key for patients to proactively stop asthma attacks and exacerbations

In Finland, a comprehensive and nationwide Asthma Programme was undertaken from 1994 to 2004 to improve asthma care and prevent the predicted increase in costs. The main goal was to less-en the burden of asthma on indi-viduals and society. “The Finnish Programme” has been followed in other countries with equally good outcomes. The implementation strategy has been adopted by the GINA Asthma Control Challenge (Figure 1).

GOALS OF THE “ASTHMA PROGRAMME”Five specific goals were set, for example, decreasing the number of days hospitalised patients by 50% and reducing annual costs per patient by 50%. The programme comprised both evidence-based management guidelines, which have been available to general practitioners and nurses via the Internet since 2000, and an ac-tion plan with defined tools to achieve the goals. The action plan focused on implementation of new knowledge, especially for primary care. At that time the new medi-cal knowledge was: “Asthma is an inflammatory disease and should be treated as such from the very beginning.” The key to implemen-

tation was an effective network of asthma-responsible professionals and development of an evaluation strategy. In 1997 Finnish pharma-cies were included in the Pharmacy Programme, and in 2002 a Child-hood Asthma Mini-Programme was launched.

RESULTS: THE BURDEN OF ASTHMA HAS DECREASEDAs a result of this programme, the burden of asthma in Finland has de-creased considerably. Key indica-tors have fallen significantly: num-

ber of hospital days with 86% from 110 000 (1993) to 15 000 (2010) and disability with 76% from 1993 to 2003 (Figure 2). In recent years, only a few asthma deaths/year under the age of 65 have been re-corded in Finland (total population 5.4 million). In young age groups there is virtually no asthma mortal-ity. In 1993 the number of patients needing regular medication for persistent asthma (entitled to 75% reimbursement of medicine costs) was around 135 000. By 2011 this number was around 239 000,

Tari Haahtela Helsinki University Hospital

Finland

EVIDENCE FOR ASTHMA CONTROL – ZERO TOLERANCE TO ASTHMA

WITH THE FINNISH PROGRAMMES 5

Ke y m e ssag e s

Evidence for asthma control – zero tolerance to asthma with the Finnish programmes

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indicating a 77% increase and re-flecting earlier and more effective detection and intervention (Figure 3). The most remarkable increase was in the use of first-line inhaled corticosteroid treatment during the early years of the programme (1994–1999).

PREVALENCE IS UP; COSTS ARE DOWNIn spite of increasing prevalence, the overall costs related to asth-ma (compensation for disability, medicines, hospital care and out-patient doctor visits) leveled off and then continued to decrease. This has been in stark contrast to what was predicted. The over-all costs of asthma in 1993 were around €330 million, including loss of productivity. By 2010, this figure had dropped to €195 million (Fig-ure 4). Based on the 1993 asthma prevalence trends, the 2010 costs would have been at least €500 mil-lion (min scenario). An estimate of the theoretical cost savings for the year 2010 alone was around €300 million. Annual costs per patient at-tributable to asthma were reduced by more than 50%. The extra costs of planning and implementing the programme were small, primarily because most of the activities were carried out as part of the routine work of the clinicians and adminis-trators.

PATIENT BENEFITS: EARLY DETECTION, TIMELY TREATMENTFor the patients with asthma, the main improvement was early de-tection of the disease and its timely treatment: “Hit early and hit hard!” Patients with chronic asthma have been educated to employ guided self-management, an approach that encourages them to be proac-tive in preventing asthma attacks and exacerbations. Effective net-

Figure 1 Simple outline for a local or national asthma implementation programme. Set a goal, decide the activities, tools and outcome measurements. “Advertise” to patients and general public with attractive and straight forward

messages: “You control asthma, asthma does not control you!”

Figure 2 Decrease in the number of hospital days and disability.

Generic Template for the Asthma Control Challenge

Quantitative (numerical) goal for health care professionals

For general public, decision makers

Tasks Tools Outcomes

For the Goal: what to do (Tasks), how to do it (Tools), and what to measure (Outcomes)?

Goal for next 5 years

Cuthospitalizations

50%! Main Messages

X Take your asthma into control X ............................................... X ............................................... X ...............................................


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working of specialists with “local asthma champions”, such as gen-eral practitioners (n=200), asthma nurses (n=700) and pharmacists (n=700) has also considerably im-proved the overall asthma care in Finland.

ExPANDING THE PROGRAMME’S SCOPEThe Finnish experience shows that it is possible to considerably re-duce the morbidity of asthma and its impact on individuals, as well as on society. Worrying trends continue to be the still slightly in-

creasing prevalence of asthma and growing drug costs. A new Allergy Programme 2008–2018, has been launched in Finland to expand the good asthma results to all allergic diseases and to take a step forward from treatment to prevention. Asthma is included with the specif-ic goal to reduce emergency visits by 40% in 10 years. For children with mild persistent asthma (the majority!), a strategy of intermit-tent (periodic) treatment has been developed. The long-term aim is to have an impact on the incidence of both asthma and allergies.

Figure 4 Decrease in asthma related costs.

KEY REFERENCES1. Haahtela T, Tuomisto LE, Pietinal-

ho A, Klaukka T, Erhola M, Kaila M, et al. A 10 year asthma programme in Finland: major change for the better. Thorax 2006;61:663-670.

2. Kupczyk M, Haahtela T, Cruz AA, Kuna P. Reduction of asth-ma burden is possible through National Asthma Plans. Allergy 2010;65:415-419.

3. Fitzgerald JM, Bateman E, Hurd S, Boulet LP, Haahtela T, Cruz AA, et al. The GINA Asthma Challenge: reducing asthma hospitalisations. Eur Respir J 2011;38:997-998.

4. Boulet LP, FitzGerald JM, Levy ML, Cruz AA, Pedersen S, Haahtela T, et al. A guide to the translation of the Global Initiative for Asthma (GINA) strategy into improved care. Eur Respir J 2012;39:1220-1229.

5. Haahtela T, von Hertzen L, Mäkelä M, Hannuksela M; Allergy Pro-gramme Working Group. Finnish Allergy Programme 2008-2018 – time to act and change the course. Allergy 2008;63:634-645.

6. von Hertzen LC, Savolainen J, Hannuksela M, Klaukka T, Lauer-ma A, Mäkelä MJ, et al. Scientific rationale for the Finnish Allergy Programme 2008-2018: emphasis on prevention and endorsing tol-erance. Allergy 2009;64:678-701.

7. Pelkonen AS, Kuitunen M, Dunder T, Reijonen T, Valovirta E, Mäkelä MJ. Allergy in children: practical recommendations of the Finnish Allergy Programme 2008-2018 for prevention, diagnosis, and treatment. Pediatr Allergy Immunol 2012;23:103-116.

8. Turpeinen M, Pelkonen AS, Sel-roos O, Nikander K, Haahtela T. Continuous versus intermittent inhaled corticosteroid (budeso-nide) for mild persistent asthma in children – not too much, not too little. Thorax 2012;67:100-102.

9. Kauppi P, Linna M, Martikainen J, Mäkelä MJ, Haahtela T. Follow-up of the Finnish Asthma Programme 2000-2010: reduction of hospital burden needs risk group rethink-ing. Thorax 2013;68:292-293.

Figure 3 Significant increase in use of asthma controller medication.

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a • The Integrated Care Pathways (ICPs) are structured multidisciplinary care plans that promote the translation of guidelines into local protocols and their subsequent application to clinical practice

• ICPs differ from practice guidelines as they are utilized by a multidisciplinary team and have a focus on the quality and co-ordination of care

• Multisectorial ICPs for rhinitis and asthma co-morbidity need to be developed and implemented combining preventive and disease control strategies, and placing a special emphasis on elderly patients and/or underserved patient populations, and on cultural and societal aspects of the diseases in a project centred around the patient

The Integrated Care Pathway (ICP) concept was initiated in 1985 by Zander and Bower. ICPs are struc-tured multidisciplinary care plans, which detail essential steps in the care of patients with a specific clin-ical problem. They promote the translation of guidelines into local protocols and their subsequent application to clinical practice. An ICP forms all or part of the clinical record, documents the care given, and facilitates the evaluation of outcomes for continuous quality improvement. ICPs empower pa-tients and their carers (health and social). ICPs differ from practice guidelines as they are utilized by a multidisciplinary team and have a focus on the quality and co-ordina-tion of care.

Asthma and allergic diseases are major chronic respiratory diseas-es and occur along the life time. People with low socioeconomic status and women bear a dispro-portionate burden. Two debates at the European Union Parliament have been organized during Presi-dencies of the EU Council (Poland: 2011, Cyprus: 2012) and stressed the importance of prevention, early diagnosis and management of chronic respiratory diseases in children. The Cyprus Presidency

debate focused on the manage-ment of chronic respiratory diseas-es in children for the promotion of active and healthy ageing.

Effectives strategies are needed to reduce asthma and allergy bur-den. (Figure 1). The Finnish Asth-ma Programme is cost-effective in different countries. However, it is insufficiently implemented and an ICP combining rhinitis and asthma comorbidity deployed in EU re-gions is a priority, as indicated by the Council of the European Union (2011). ARIA (Rhinitis and Asthma co-morbidity) is a co-morbidity guideline initiated in 1999 in col-

laboration with the World Health Organisation (WHO). It has been developed using GRADE (Grading of Recommendations, Assessment, Development and Evaluation) and variance analysis and is available in many countries.

Integrated Care Pathways for rhi-nitis and asthma need to be devel-oped and implemented. The ob-jectives of AIRWAYS-ICP are (i) to develop multisectoral ICPs which can be used across Europe and oth-er countries, (ii) to allow the prac-tical use of a combined asthma and allergy programme by European countries and regions, (iii) to com-

Jean Bousquet University of Montpellier

France

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THE POLITICAL AGENDA6

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The need for integrated and complimentary strategies in the political agenda

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The need for integrated and complimentary strategies in the political agenda

bine preventive and disease con-trol strategies, (iv) to place a spe-cial emphasis on elderly patients and/or underserved patient pop-ulations, (v) to implement cost-ef-fective policies on prevention of asthma and allergy and (vi) to have an impact on active and healthy ageing. AIRWAYS-ICP places a particular interest in cultural and societal aspects of the diseases in a project centred around the patient.

Patient’s organisations and major European scientific societies are partners of the WHO Collabora-tive Center for Asthma and Rhinitis for this initiative.

KEY REFERENCES1. Zander K. Historical development

of outcomes-based care deliv-ery. Crit Care Nurs Clin North Am 1998;10:1-11.

2. Bousquet J, Tanasescu CC, Camu-zat T, Anto JM, Blasi F, Neou S, et la. Impact of early diagnosis and

control of chronic respiratory diseases on active and healthy ageing. A debate at the European Union Parliament. Allergy 2013; 68: 555-561.

3. Overill S. A practical guide to care pathways. J Integr Care 1998;2:93-98.

4. Samoliński B, Fronczak A, Włodarczyk A, Bousquet J. Council of the European Union conclusions on chronic respira-tory diseases in children. Lancet 2012;379:e45-46.

5. Council conclusions on Healthy Ageing across the Lifecycle. 3206th employment EMPLOY-MET, SOCIAL POLICY, HEALTH and COSUMER AFFAIRS Council meeting. Brussels, 7 December 2012. http://www.consilium.eu-ropa.eu/uedocs/cms_data/docs/pressdata/en/lsa/134097.pdf, ac-cessed May 20, 2013.

6. European Innovation Partner-ship. Active and Healthy Ageing. http://ec.europa.eu/research/innovation-union/index_en.cfm?-

section=active-healthy-ageing, accessed May 20, 2013.


8. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008;63 Suppl 86:8-160.

9. Brozek JL, Bousquet J, Baena-Cag-nani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010;126:466-476.

10. Haahtela T, von Hertzen L, Mäkelä M, Hannuksela M; Allergy Pro-gramme Working Group. Finnish Allergy Programme 2008-2018--time to act and change the course. Allergy 2008;63:634-645.

Figure 1 The Integrated Care Pathway for Asthma.

Cost-efficient use of resources

development of care partnerships

clinical governance empower patients and their carers

target the intervention to the individual needs

cultural and societal aspects

The Integrated Care Pathway for asthma

translation of guidelines into local protocols

manage riskefficacious application into clinical practice

Asthma prevention and control

Better quality of life

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a • Create awareness for early recognition of asthma• Provide easily accessible facilities for asthma diagnosis and

treatment• Create awareness for early recognition of asthma triggers and

their prevention• Develop workable strategies for facilitating access to asthma

diagnosis and treatment• Develop global, regional, national and local policies to improve

asthma diagnosis and treatment• Develop, promote and ensure the use of evidence based guidelines

for asthma diagnosis and treatment• Empower people with asthma to participate and make choices

about asthma care and to lobby for better treatment and prevention health policies

Asthma ranks amongst the com-monest diseases globally. Its prev-alence is increasing, but at the same time access to asthma diag-nosis and treatment lacks behind the burden of disease. It is a major disease in low and middle income countries, and unfortunately still remains under-recognised, un-der-diagnosed and therefore, un-der-treated, or sometimes even over-treated.

Effective policies and strategies are needed to fill this gap and fa-cilitate access to the diagnosis and treatment of asthma. These are necessary at the global, regional, national and local level. These must be dispersed widely and proper im-plementation must be ensured to be effective.

GLOBAL AND REGIONAL POLICIES AND PROGRAMMES FOR ASTHMA

1. The United Nations – Non Com-municable Diseases Agenda

The United Nations (UN) recog-nized the global importance of Non Communicable Diseases (NCDs) and the place of Chronic Respira-tory Diseases (CRD), including asthma, as being responsible for more deaths than all other causes combined.

2. The WHO NCD Action Plan 2008-2013

The World Health Organisation (WHO) recommended a 5 year NCD Action Plan in 2008 (Table 1).

3. Global Alliance against Chronic Respiratory Diseases (GARD)

GARD is a voluntary alliance of national and international organ-izations, institutions and agencies from many countries working to-wards the common goal of reduc-ing the global burden of CRDs, in-cluding asthma. Its vision is a world where all people breathe freely (Figure 1).

4. The International Union against Tuberculosis and Lung Disease (The Union)

The Union’s approach to asthma management is adapted from in-ternational asthma guidelines and uses a framework based on The Un-ion’s model for tuberculosis servic-es. This framework advocates for standard case management, use of simple tools for the diagnosis and classification of the asthma sever-ity, careful monitoring and evalua-tion of asthma care, and provision of essential medicines through it’s Asthma Drug Facility, as a practical solution to this problem.

Osman M. Yusuf The Allergy & Asthma Institute

Islamabad, Pakistan

POLICIES AND STRATEGIES TO FACILITATE ACCESS TO ASTHMA

DIAGNOSIS AND TREATMENT7

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TABLE 1

Global action plans and barriers to improving asthma care

NCD Action Plan

Act

ion

po

ints

1. Raise the priority accorded to non-communicable disease (NCDs) at global and national levels

2. Establish and strengthen national policies and plans for the prevention and control of NCDs

3. Promote interventions to reduce the main shared modifiable risk factors: tobac-co use, unhealthy diets, physical inactivity and harmful use of alcohol

4. Promote research for the prevention and control of NCDs

5. Promote partnerships for the prevention and control of NCDs

6. Monitor NCDs and their determinants and evaluate progress at the national, regional and global levels

Global Initiative for Asthma (GINA)

Act

ion

po

ints

1. Evidence-based guidelines must be effectively implemented and disseminated at the national and local levels

2. Implementation of asthma guidelines should involve a wide variety of profes-sional groups and other stakeholders, including patient groups and organiza-tions, policy makers and planners, and others.

3. Asthma guidelines should take into account local cultural and economic condi-tions

4. Evaluate the effectiveness and quality of care

5. Adaptation and implementation of asthma guidelines require an understanding of the cost and cost effectiveness of various management recommendations in asthma care.

6. Access to available and affordable medication, especially in LMIC; cost should not be a barrier to achieve asthma control.

Brussels Declaration from the European Summit for Change in Asthma Management

Act

ion

po

ints

1. Make asthma a political priority

2. Understand that, in addition to local mechanisms, asthma is a respiratory mani-festation of systemic inflammation

3. Ensure rapid responses to the most current scientific understanding of asthma

4. Update the European Medicines Agency (EMA) regulatory guidance on asthma

5. Include evidence from real-world studies in treatment guidelines

6. Provide funding for real-world studies

7. Explore variations in asthma care across Europe

8. Enable people with asthma to participate and make choices about their care

9. Understand and reduce the impact of environmental factors

10. Set targets to assess improvements

Barriers to Improving Asthma Care

Act

ion

po

ints

The Union

• lack of political commitment to fund non-communicable diseases

• lack of structure or organization for following up patients with chronic disease

• high cost of equipment and essential medicines

• lack of personnel trained to manage asthma

• health services oriented for acute care are unable to organize the long-term management needed for asthma care

GINA: Evidence based guidelines can become ineffective, if there is:

• Poor infrastructure to use recommended medications

• Suboptimal use of medications

• Lack of physicians use of guidelines

5. The International Primary Care Respiratory Group (IPCRG)

Primary care is the cornerstone of a health system being pivotal in prevention, diagnosis, patient en-gagement and supported self-man-agement, and treatment of asthma. Integration between primary and secondary care is essential for fa-cilitating access to asthma diagno-sis and treatment.

6. Global Asthma Network (GAN)

This new network, launched in No-vember 2012, aims to improve care for people with asthma around the world. A world without asthma is the ultimate goal of the GAN.

7. The Global Initiative for Asthma (GINA)

Patient care following evi-dence-based asthma guidelines leads to improved outcomes. Im-plementation of asthma guidelines should include setting of goals and development of strategies through collaboration amongst diverse pro-fessional groups including both primary and secondary health care professionals, public health offi-cials, patients, asthma advocacy groups, and the general public (Ta-ble 1).

Goals and implementation strate-gies vary from country to country and within countries for reasons of economics, culture, and envi-ronment. The priority ranking of asthma amongst other diseases, especially in low- and middle in-come countries (LMIC), must be increased (Figures 2-4).

8. Allergic Rhinitis and its Impact on Asthma (ARIA)

Rhinitis is the most common NCD among children. Asthma and rhini-tis often co-exist, and it is impor-tant to recognize, diagnose and treat rhinitis to prevent the devel-

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Figure 1 Countries with Global Alliance for Respiratory Diseases

(GARD) programmes and activities. (Reproduced from Bousquet J, GARD

General Meeting, Istanbul, 30-31 May 2008)

Figure 2 GINA Member countries

Figure 3 Countries having asthma guidelines for adults

Figure 4 Countries having asthma guidelines for children.


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opment to asthma or to improve asthma control.

9. The Brussels Declaration

The Brussels Declaration on Asth-ma was developed to call attention to the shortfalls in asthma manage-ment and to urge European policy makers to recognise that asthma is a public health problem that should be a political priority (Table 1).

The diagnosis of asthma is diffi-cult. It is important to understand

that the diagnosis and treatment of asthma of children is different from adults. There should be ade-quate access to the diagnosis and treatment of comorbidities as well.

STRATEGIESStrategies for facilitating access to diagnosis must focus on creating awareness and recognition of asth-ma at all levels of society, includ-ing the general public, students, patients and other stake-holders.

Physicians and health care work-ers must be trained for early and accurate diagnosis, taking the cor-rect history, and managing treat-ment according to the availability of therapies and their affordability by the patient. They have to be tai-lor-made according to the specific requirements of each and every patient.

Strategies for facilitating access to asthma diagnosis and treatment are highlighted in Figure 5.

General PublicRecognition of

symptoms of asthma

• Informative literature & stories• Articles in lay press• Public lectures on asthma• Asthma camps in carnivals, funfairs & public events, including free spirometry/PEFR• Media events, talk shows on radio, TV and other electronic media• Celebration of World Asthma Day and other similar events• Promote Asthma Champions in the community• Disseminate information about periods of asthma exacerbation: pollen season, dust

storm season, wheat-threshing season etc.

School Health Programs

Students

Awareness about early recognition of symptoms

School Health Teams

School Administration

• Train to recognize symptoms of asthma• Understand the importance of diagnosing and treating rhinitis to prevent asthma and to

improve its control• Training in management of asthma:

� Preventative treatment � Managing an exacerbation

School Health Programs• Establish management & support systems for Asthma-Friendly Schools• Provide appropriate school health & mental health services for students with asthma• Provide asthma education & awareness programmes for students and school staff• Provide a safe and healthy school environment to reduce asthma triggers• Provide safe, enjoyable physical education and activity for students with asthma• Coordinate school, family and community efforts to better manage asthma symptoms

and reduce school absences among students with asthma

Figure 5 Strategies to facilitate access to asthma diagnosis and treatment. (Continued on next page)

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Physicians & Health-care Workers

General Practitioners

Specialist

• Should be easily accessible to the patient• Should be properly trained to diagnose and manage asthma, as per

evidence based guidelines• The GPs should evaluate using SIMPLES

S: smoking statusI: Inhaler: technique & deviceM: monitor asthma controlP: pharmacotherapy including adherence to treatmentL: lifestyle, including exposure to triggers of asthma and allergensE: Education- check whether the patient understands his illness, its control and management, including self-management plans and use of appropriate technologyS: Support- check patient’s support from his family, friends and car-egivers and their understanding of proper compliance to therapy

• Should know when to refer to a specialist and write a proper referral letter

• Be accessible for referred patients for confirmation of diagnosis and review the treatment

• Provide adequate diagnostic services e.g. spirometry, allergy testing, occupational allergy etc.

• Prepare a comprehensive treatment plan and explain to the GP and the patient

• Strengthen the skills of the family health team (doctors, nurses and other health care workers)

KEY REFERENCES 1. From the Global Strategy for

Asthma Management and Preven-tion. Global Initiative for Asthma (GINA), 2012. Available from: www.ginasthma.org.

2. Position Paper 1 Primary care and chronic lung disease. Internation-al Primary Care Respiratory Group, 2913. http://www.theipcrg.org, accessed May 20, 2013.

3. Holgate S, Bisgaard H, Bjermer L, Haahtela T, Haughney J, Horne R, et al. The Brussels Declaration: the need for change in asthma management. Eur Respir J 2008; 32:1433–1442.

4. Asthma. The International Union against Tuberculosis and Lung Dis-eases. http://theunion.org, ac-cessed May 20, 2013.

5. Global Asthma Report 2011. Par-is, France: The International Union Against Tuberculosis and Lung Dis-ease, 2011.

6. Improving the care of adults with difficult to manage asthma: a prac-tical guide for primary healthcare professionals. Desktop Helper. In-ternational Primary Care Respirato-ry Group, 2012. http://www.theip-crg.org, accessed May 20, 2013

Patients Education

Management

• Early recognition of symptoms and their control• Knowledge of triggers and allergens and their control• Information about comorbidities

• Self-management plans; includes the use of latest technologies• Access to available and affordable medicines including inhalers & devices• Knowledge of when to see the doctor or emergency• For children: educate parents, caregivers

Policy Makers In consultation with asthma stakeholders, including patients and associations:• Arrange easy and affordable access to asthma diagnosis and treatment facilities• Establish/ support asthma and allergy clinics• Arrange National Asthma Committees• Support preparation and dissemination of National Asthma Guidelines• Smoking Cessation Policies: legislation & enforcement• Asthma Surveillance Activities including environmental allergen/pollen monitoring• Collaboration with International and regional Asthma programs• Provision of low cost medicines, diagnosis and treatments, especially in LMIC• Arrange reimbursement for asthma therapies

Figure 5 Strategies to facilitate access to asthma diagnosis and treatment. (Continued from previous page)


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• A wide variety of factors are known to precipitate attacks of asthma in affected individuals and many of these factors can be controlled by implementation of effective public policies

• Public policies in controlling outdoor and indoor air pollution can reduce asthma morbidity and even mortality

• Burning of biomass is an important contributing factor to respiratory health and asthma morbidity especially in developing countries

• Public policies in controlling environmental tobacco smoke exposure reduce asthma morbidity

Many factors are known to be trig-gers of asthma exacerbations in patients with asthma. Much less is known regarding the factors that may cause asthma. Although ge-netic factors are likely to be impor-tant in the development of asthma, the rapid increase of asthma with urbanization clearly points to the importance of environmental fac-tors in the pathogenesis of asthma. Indoor and outdoor air pollution, tobacco smoke exposure, school environment, potential toxic ex-posure are all factors which may contribute to asthma morbidity. Ef-fective implementation of related public policies may help to reduce the morbidity and to minimize the societal cost of asthma control.

OUTDOOR AIR POLLUTION AND ASTHMAOutdoor air pollution is mostly gen-erated from burning of biomass fu-els and exhausts of motor vehicles. Increase in the levels of different air pollutants are known to induce inflammation within the asthmatic airways resulting in narrowing of the airways, deterioration of lung function, asthma attacks, hospital-ization, and even death. As there is no threshold level of so called safe levels, efforts should try to reduce the levels to the lowest possible

(Table 1). Traffic pollution (Figure 1) is becoming increasing impor-tant in both developing and devel-oped countries. Research studies have shown that children who live close to a freeway are at higher risk of developing asthma. As children spend most of their time at schools during the day in California, schools are not allowed to be built with-in 500 feet from a freeway. Public policies to reduce emissions from power plant and control of diesel powered vehicles can reduce sig-nificantly outdoor air pollution. Establishment and adoption of air quality guidelines are important in helping to set national goals for reducing levels of air pollutants for the benefits of patients with asth-ma and other respiratory diseases.

Gary W.K. Wong Chinese University of Hong Kong

China

POLICIES AND STRATEGIES TO REDUCE RISK FACTORS FOR

ASTHMA8

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Figure 1 Traffic pollution affects all ages

Policies and strategies to reduce risk factors for asthma

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TABLE 1

European Ambient Air Quality Standards *

Pollutant Concentration (µg/m3) Averaging period

Fine articles (PM2.5) 25 1 year

Sulphur dioxide (SO2)

350 1 hour

125 24 hours

Nitrogen dioxide (NO2)

200 1 hour

40 1 year

PM1050 24 hours

40 1 year

Carbon monoxide (CO) 10 Maximum daily 8 hour mean

Ozone 120 Maximum daily 8 hour mean

* From European Commission Ambient Air Quality Standards. http://ec.europa.eu/environment/air/quality/standards.htm, accessed May 20, 2013.

INDOOR AIR POLLUTIONEnvironmental tobacco smoke (ETS) exposure and emissions from burning of biomass fuels in poor-ly ventilated homes are the most important causes of indoor air pollution (Figure 2). Exposure to pollution related to use of biomass fuels have been associated with lower respiratory tract infections in children, asthma symptoms in children and adults, as well as low-er lung function in exposed adults. Research has also shown that im-provement of the design of bio-mass stove can reduce indoor air pollution leading to improvement of lung function of people living in such households. With regards to the adverse effects of ETS expo-sure, children and the fetus are at higher risk of the effects. Public policies in reducing second hand tobacco smoke both in public are-as as well as areas where there are children would be important in re-ducing the detrimental influences especially on asthmatics subjects. Poor ventilation and sanitation in households or school can result in excessively high level of allergens (such as indoor molds) which can precipitate asthma attacks in sus-ceptible individuals. Public policies governing building codes and lev-els of sanitation are important in protecting susceptible individuals.

WORK-RELATED ASTHMAWorkers in a wide range of occu-pations or industries are at high-er risk of development of asthma. These include bakers, forestry, textiles, rubber, chemical and elec-trical production workers. Due to the job nature, exposure to differ-ent irritants, allergens, or chemi-cals results in inflammation of the airways and asthma. Public policies in setting standards in reducing ex-posure for related occupations or industries are of paramount impor-

tance in the primary and secondary prevention of work related asthma.

KEY REFERENCES1. Kelly FJ, Fussell JC. Air pollution

and airway disease. Clin Exp Allergy 2011;41:1059-1071.

2. European Commission Ambient Air Quality Standards. http://ec.europa.eu/environment/air/quality/standards.htm, accessed

May 20, 2013.

3. Pietinalho A, Pelkonen A, Rytilä P. Linkage between smoking and asthma. Allergy 2009;64:1722-1727.

4. Moscato G, Pala G, Barnig C, De Blay F, Del Giacco SR, Folletti I, et al. EAACI consensus statement for investigation of work-related asthma in non-specialized centres. Allergy 2012;67:491-501.

Figure 2 Sources of indoor pollution.

Policies and strategies to reduce risk factors for asthma

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• Prevalence rates for active cigarette smoking in adolescents and adults with asthma are similar to the general population

• Active cigarette smoking and exposure to second-hand smoke are risk factors for the development of asthma and are associated with poor asthma control, exacerbations and hospital admissions and an accelerated decline in lung function

• Tobacco control offers a major opportunity to prevent and improve health care outcomes in asthma

• Smoking cessation is an important goal in the management of smokers with asthma and in the parents of children with asthma

• Legislation to control cigarette smoking in public places improves asthma control in both children and adults

ASTHMA AND THE ADVERSE EFFECTS OF SMOKINGPrevalence rates for active ciga-rette smoking in adolescents and adults with asthma are similar to those in the general population (Figure 1).

Exposure to second-hand smoke and active smoking has a major adverse health impact in asthma. Maternal smoking, both during and after pregnancy, increases the risk of asthma among children. In adolescents and adults exposure to second-hand smoke is also as-sociated with the development of asthma. In both children and adults with asthma, exposure to sec-ond-hand smoke is associated with worse clinical outcomes (Table 1) and higher health care costs.

Smokers with asthma have worse asthma control, poorer quality of life, more frequent exacerbations and hospital admissions, as well as an accelerated decline in lung func-tion compared to never-smokers with asthma (Figure 2). In addition, active cigarette smoking is associ-ated with a reduced therapeutic response to corticosteroids, which may contribute to the adverse ef-fects of cigarette smoking in asth-ma.

TOBACCO CONTROLThe World Health Organization’s (WHO) Framework Convention on Tobacco Control is being im-plemented worldwide to improve health outcomes in the general population. Tobacco control in so-ciety offers a major opportunity to prevent asthma and improve symp-tom control in people with asthma through reduction in exposure to tobacco smoke, both direct and second-hand. A key component of the WHO initiative involves the implementation of the ‘MPOWER’ policy on tobacco control (Table 2), and some of these measures have been shown to impact positively on health outcomes in asthma.

PROTECT PEOPLE WITH ASTHMA FROM TOBACCO SMOKEStopping parental smoking is an es-sential component to reducing the risk of developing of asthma. Pre-venting exposure to second-hand smoke should begin before child birth and throughout childhood. Smoking cessation programmes in parents of children with asthma may reduce the burden of emer-gency events due to exposure to second-hand smoke, although the benefit of extensive interventions designed to reduce smoking rates on asthma outcomes has not been established. Reducing maternal smoking before conception or

Neil C. Thomson University of Glasgow

UK

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Figure 1 Proportion of adults ages 15 years or older who currently smoke cigarettes and other tobacco products and number of current tobacco smokers (in millions), by sex, for the UK, USA, and 14 GATS countries GATS-Global Adult

Tobacco Survey. (Reprinted from The Lancet, 380, Giovino GA, Mirza SA, Samet JM, et al, Tobacco use in 3 billion individuals from 16 countries: an analysis of nationally representative cross-sectional household surveys, 668-679, Copyright 2012, with permission

from Elsevier.)

52.9% (288.1 million)2.4% (12.6 million)

24.3% (99.9 million)2.9% (11.3 million)

44.7% (21.2 million)1.5% (0.7 million)

47.4% (14.8 million)1.4% (0.5 million)

47.6% (14.6 million)9.0% (2.8 million)

45.6% (11.7 million)3.1% (0.8 million)

60.2% (30.6 million)21.7% (13.3 million)

50.0% (9.1 million)11.3% (2.5 million)

36.9% (5.7 million) 24.4% (4.1 million)

37.6% (9.5 million)0.5% (0.1 million)

47.9% (12.0 million)15.2% 4.0 million)

21.6% (14.8 million)13.1% (9.8 million)

24.8% (8.1 million)7.8% (2.8 million)

30.7% (0.4 million)19.8% (0.3 million)

22.8% (4.5 million)20.6% (4.6 million)

24.0% (26.8 million)16.2% (19.4 million)

China

India

Bangladesh

Vietnam

Phillippines

Thailand

Russia

Ukraine

Poland

Egypt

Turkey

Brazil

Mexico

Uruguay

UK

USA

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in early pregnancy may have the greatest effect on preventing the development of asthma. Legisla-tion to control cigarette smoking in public places results in improve-ments in symptom control for adults with asthma and in rate of hospital admission with acute asth-ma in children (Figure 3).

OFFER HELP TO QUIT TOBACCO USE IN ASTHMASmoking cessation is an important goal in the management of smok-ers with asthma. A small number of studies have examined the role of smoking cessation on asthma out-comes and reported improvements in symptoms and lung function in those people who quit smoking successfully. In addition, former smokers with asthma have better asthma control than ex-smokers with asthma. Despite the known adverse effects of active smoking in asthma, this group are no more likely to receive physician counsel-ling regarding smoking cessation, nor smoking cessation pharmaco-therapy compared to the general smoking population.

Figure 2 Interaction of active cigarette smoking and asthma. (Reproduced from Thomson N, Chaudhuri R, Livingston E. Active cigarette smoking and asthma. Clin Exp

Allergy 2003;33:1471-1475 with permission from John Wiley and Sons, Inc.)

TABLE 2

WHO MPOWER policy on tobacco control

• Monitor tobacco use and prevention policies

• Protect people from tobacco smoke

• Offer help to quit tobacco use

• Warn about the dangers of tobacco

• Enforce bans on tobacco advertising, promotion and sponsorship

• Raise taxes on tobacco

TABLE 1

Exposure to second-hand smoke is associated with increased health care utilisation in adults with non-severe asthma *

No exposure to second-hand smoke (n=252)

Exposure to second-hand smoke (n=108)

Odd Ratio (95% CI)

p value

Intensive Care Unit Admission 11 (4.4%) 19 (17.6%) 4.7 (2.2 to 10.5) <0.001

Night in hospital 69 (27.1%) (40 (37.7%) 1.6 (1.0 to 2.6) 0.04

Urgent Care visit due to asthma 51 (20.0%) 32 (30.2%) 1.8 (1.0 to 2.9) 0.03

Assisted Ventilation 5 (2.0%) 11 (10.4%) 5.8 (2.1 to 18.9) <0.001

Emergency Room visit for breathing problem

31 (12.2%) 26 (23.9%) 2.3 (1.3 to 4.0) 0.006

* Reproduced from Comhair SA, Gaston BM, Ricci KS, et al. Detrimental Effects of Environmental Tobacco Smoke in Relation to Asth-ma Severity. PLoS ONE 2011;6:e18574.All data are presented in No (%).

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Figure 3 Daily hospital admissions for asthma among children between January 2000 and October 2009. Ban on smoking in public places in Scotland was initiated in 2006 ( From N Engl J Med, Mackay D, Haw S, Ayres JG, et al. Smoke-free legislation

and hospitalizations for childhood asthma, 363, 1139-45 Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

ExAMPLE OF WHO MPOWER POLICY ON TOBACCO CONTROL IN PRACTICEA comprehensive tobacco-con-trol campaign in a low-income to middle-income country (Uruguay) that included actions such as the banning of tobacco advertising, the banning of smoking in all enclosed public spaces, tax increases, and legislation requiring health warn-ings on cigarette packets resulted in a substantial reduction in tobac-co use. Implementation of similar policies should result in improved health for the general population as well as for people with asthma, or those who are at risk of develop-ing asthma.

KEY REFERENCES1. Thomson NC. The role of en-

vironmental tobacco smoke in the origins and progression of asthma. Curr Allergy Asthma Rep 2007;7:303-309.

2. Comhair SA, Gaston BM, Ricci KS,

Hammel J, Dweik RA, Teague WG, et al. Detrimental Effects of Envi-ronmental Tobacco Smoke in Rela-tion to Asthma Severity. PLoS ONE 2011;6:e18574.

3. Thomson N, Chaudhuri R. Asthma in smokers: challenges and op-portunities. Curr Opin Pulm Med 2009;15:39-45.

4. WHO report on the global tobac-co epidemic 2011: warning about the dangers of tobacco. Geneva: WHO Press, 2011.

5. Menzies D, Nair A, Williamson PA, Schembri S, Al-Khairalla MZ, Barnes M, et al. Respiratory symp-toms, pulmonary function, and markers of inflammation among bar workers before and after a leg-islative ban on smoking in public places. JAMA 2006;296:1742-1748.

6. Mackay D, Haw S, Ayres JG, Fis-chbacher C, Pell JP. Smoke-free Legislation and Hospitalizations for Childhood Asthma. N Eng J Med 2010;363:1139-1145.

7. Giovino GA, Mirza SA, Samet JM, Gupta PC, Jarvis MJ, Bhala N, et

al. Tobacco use in 3 billion individ-uals from 16 countries: an anal-ysis of nationally representative cross-sectional household sur-veys. Lancet 2012;380:668-679.

8. Thomson N, Chaudhuri R, Liv-ingston E. Active cigarette smok-ing and asthma. Clin Exp Allergy 2003;33:1471-1475.

9. To T, Stanojevic S, Moores G, Ger-shon A, Bateman E, Cruz A, et al. Global asthma prevalence in adults: findings from the cross-sec-tional world health survey. BMC Public Health 2012;12:204.

10. Thomson NC, Chaudhuri R, Heaney LG, Bucknall C, Niven RM, Brightling CE, et al. Clini-cal outcomes and inflammatory biomarkers in current smok-ers and exsmokers with severe asthma. J Allergy Clin Immunol 2013;131:1008-1016.

11. Spears M, Cameron E, Chaudhuri R, Thomson NC. Challenges of treating asthma in people who smoke. Expert Rev Clin Immunol 2010;6:257-268.


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• The increased incidence and prevalence of asthma is multifac-torial and includes epigenetic mechanisms and lifestyle factors: changes in the traditional diet, physical inactivity and stress

• Asthma has been associated with reduced physical activity, but also with high-intensity long-term exercise, as seen in athletes. As the benefits of regular, moderately intense aerobic exercise have been demonstrated in allergic asthma, there is no reason to discourage asthmatics with controlled disease from regular exercise

• The increase in obesity, a known risk factor for metabolic and cardiovascular diseases, also increases the risk of incident asthma and of a difficult-to-control asthma phenotype

• Adherence to a Mediterranean diet associates better asthma control in adults and, during pregnancy, decreased risk of asthma symptoms in the offsprings. Achieving a balanced healthy diet is recommended for weight management and overall health, and as part of a multidisciplinary asthma management plan

A consistent body of literature shows a positive association be-tween the increased incidence and prevalence of atopic diseases, including asthma, and the west-ernized lifestyle. This seems to be more notorious after the Second World War and may have recent-ly reached a plateau. Explanations for this association have been pos-tulated and the most consistent ones include the decreased micro-bial exposure throughout life. With increased sanitation and hygiene, the progressive reduction or lack of exposure to a wide range of mi-crobiota impairs immune regula-tory mechanisms increasing the chance of immune dysfunction. This parallels with an increase in several chronic noncommunica-ble disorders - e.g. asthma and allergic diseases, diabetes and au-to-immune disorders, metabolic (obesity and type 2 diabetes) and cardiovascular disease, cancer - all sharing underlying immune-regu-latory dysfunction and low-grade, subclinical, chronic inflammation (Figure1).

However, it seems unlikely that the cause of the allergic epidemic rely in just one major factor. It should be multifactorial and include con-tributions from epigenetic mecha-

nisms - the plastic interaction of a genetic background with changing environment factors (microbiota, nutrients, allergens, pollutants) - and lifestyle factors - changes in the traditional diet, physical inac-tivity and stress.

Diet and physical activity influence health both together and separate-ly. Although the effects of diet and physical activity on health often interact, particularly in relation to obesity, there are additional health

benefits to be gained from physical activity that are independent of nutrition and diet, and also signif-icant nutritional factors that are unrelated to obesity.

PHYSICAL ACTIVITY AND ASTHMAPhysical activity is a fundamen-tal way to improve the individual physical and mental health. The relationship between physical activity and asthma seems a par-adox. Heavy physical activity has

IMPLEMENTATION OF A HEALTHY LIFE STYLE AND

ASTHMA10

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Figure 1 The increased prevalence of chronic noncommunicable disorders (including allergy and asthma) with westernized lifestyle. The reduced exposure to a diverse microbioma and physical inactivity may impair immune regulatory

mechanisms increasing the chance of immune dysfunction.

been related to asthma occurrence and exacerbation. In elite athletes asthma is diagnosed more fre-quently than in the general popu-lation. This has been attributed to airway inflammation and increased bronchial responsiveness induced by high-intensity long-term exer-

cise, like long-distance running or competitive swimming (Figure 2). Exercise is also a powerful trigger of asthma symptoms and may re-sult in asthmatic patients avoiding activity with detrimental conse-quences to their physical and so-cial well-being. However, reduced

Figure 2 Exercise and asthma. The relationship between exercise and asthma seems a paradox. Asthma has been associated with reduced physical activity

but also with high-intensity long-term exercise, as seen in elite athletes or competitive swimming. So, with exercise “less is more”: the best way to increase

activity levels is to spend more time on moderate-intensity exercise and less on high-intensity activity. (Reproduced from Haahtela T, Malmberg P, Moreira

A. Mechanisms of asthma in Olympic athletes--practical implications. Allergy 2008;63:685-94, with permission from Wiley-Blackwell.)

physical activity has been associ-ated with increased asthma preva-lence, and moderate regular phys-ical activity has been suggested to prevent disease progress.

Physical training may reduce breathlessness and asthma symp-toms by strengthening respiratory muscles and decreasing ventila-tion rate during exercise. Although training programs in asthma have not improved lung function in controlled trials, positive effects on the allergic inflammation have been showed (Figure 3). The ben-efits of moderately intense aero-bic exercise have also been shown in experimental models of allergic asthma, with attenuation of the Th2 mediated inflammatory re-sponses in the lung.

THE OBESITY AND ASTHMA EPIDEMICSObesity prevalence is the easiest way to evaluate changes in diet and physical activity. According to most recent data obesity and over-weight have reached epidemic pro-portions in westernized countries. In Europe prevalence of obesity has raised threefold or more since the 1980’s, even in countries with traditionally low rates, and in the United States, obese or overweight subjects represent more than two thirds of the adults. The relevance of obesity as a risk factor for dis-eases, including type2 diabetes, hypertension, and atherosclero-sis has been recognized for a long time. In the last decade, increasing evidence shows that obesity in-creases the risk of incident asth-ma and alters its course towards a more difficult-to-control pheno-type.

Recent meta-analyses showed that overweight and obesity are asso-ciated with increase in the odds of incident asthma, in a dose-depend-

Westernised life style

• Sanitation• Hygiene• Physical inactivity• Refined & highly

processed diet• Urban environment

Chronic Non- Communicable Diseases

• Allergy & asthma• Diabetes &

autoimmune diseases• Atherosclerosis &

cardiovascular diseases• CancerMicrobiota

diversity

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Risk factors Mechanisms Effects

Frequency and duration of training

Dosage chloraminesAge of first exposure

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Airway inflammationAutonomic nerve dysregulation

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Figure 4 The obesity-asthma link. Obesity is the product of dietary and physical activity changes in lifestyle. Inflammatory mediators produced by adipose

tissue modulate the immune responses in the lung, while chronic low-grade inflammation of the obese influence the susceptibility to airway obstruction. Animal experiments suggest that both the increases in serum leptin and the decreased serum adiponectine observed in obesity may exacerbate airway

inflammation. Obesity also causes a reduction in lung volumes, compliance, and peripheral airway diameter, as well as an increase in airway responsiveness, changes in pulmonary blood volume, and a ventilation–perfusion mismatch.

Inflammatory & immune mechanisms

Low grade inflammation

Increased TNFα, IL-1β, IL-6, leptin

Decreased adiponectin

Mechanical unloadingReduction in lung volumes &

complianceDecrease in airway caliberInhibition of deep breath

Figure 3 Physical activity and asthma. A randomized controlled study showed that engagement of asthmatic children in physical training does not worsen

allergic inflammation or asthma outcomes and suggests a possible positive effect in IgE mediated allergy. (Data from Moreira A, Delgado L, Haahtela T, et al. Physical

training does not increase allergic inflammation in asthmatic children. Eur Respir J 2008;32:1570-5.)

ent manner, and that weight gain, as much as required to become obese, almost doubles the odds of incident asthma. The relation between obesity and asthma has been traditionally explained by both inflammatory and mechanical pathways (Figure 4). Taken togeth-er, these observations support the recommendation of weight control and tackling obesity as part of an asthma management plan.

DIETARY PATTERNS AND ASTHMAThe remarkable variation in asth-ma prevalence between countries or geographically adjacent areas suggests that environmental fac-tors play a determinant role both in asthma prevalence and severi-ty. The marked changes in dietary patterns in recent decades – e.g. decreased intake of antioxidant micronutrients from fruits and vegetables and changes in fatty acids profile – may explain some of these variations.

Several epidemiological studies have reported beneficial associa-tions for higher intake of nutrients that may be relevant in the redox mechanisms and immunomodu-lation, such as vitamins A, D, and E, selenium, magnesium, zinc and n-3 polyunsaturated fatty acids (PUFA), also observed for foods sources of these micronutrients, such as fresh fruits, vegetables, nuts, and fatty fish. However, in-terventions with supplementation of single nutrients in asthma have been disappointing, and current-ly there is no evidence to support its use. Dietary exposure should be considered as a whole to un-derstand the possible synergistic effects between nutrients in foods and specific dietary patterns.

Mediterranean diet, a well-recog-nized cultural model for healthy

-30 -20 -10 10

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Figure 5 The beneficial link between the Mediterranean dietary pattern and adult asthma. MUFA - monounsaturated fatty acids; SFA - saturated fatty

acids. Odds ratios between mediterranean diet and asthma control. The results suggest that high adherence (H) to Mediterranean diet (aMED Score) and of its

typical foods, such as fresh fruits and nuts, reduces asthma severity in adults. (Reproduced from Barros R, Moreira A, Fonseca J, Adherence to the Mediterranean

diet and fresh fruit intake are associated with improved asthma control. Allergy 2008;63:917-23, with permission from Wiley-Blackwell.)

eating, has been associated with low incidence of mortality and morbidity by chronic diseases in Mediterranean populations, com-paratively to the US or Northern Europe. A similar north-south gradient has been observed for asthma, with some countries such as Greece or Albania, presenting the lowest prevalence. Adherence to Mediterranean diet and fresh fruit intake has been shown to in-crease the likelihood of asthma being under control (defined by symptoms, lung function and air-way inflammation), while higher intake of ethanol increased the risk

of uncontrolled asthma (Figure 5). Higher intakes of nuts was asso-ciated with better lung function, and additionally dietary intake of n-3 PUFA, namely alpha linolenic acid, was also associated with good asthma control. Other factors of the traditional Mediterranean life-style, linked with small-scale farm-ing of fruits, vegetables, and sun exposure, may also play a role. Re-duced exposure to soil microbiota in urban environment was coined as a major facilitator of the “allergy epidemic” while the consumption of self-produced vegetables might protect against atopic conditions.

aMED Score

Ratio MUFA/ SFA

Ethanol

Red meats

Fish

Whole grains

Nuts

Fruit

Pulses

Vegetables

HMLHMLHMLHMLHMLHMLHMLHMLHMLHML

0.1 10

Controlled Non-controlled

OR (95%CI)1

p-trend=0.015

p-trend=0.035

p-trend=0.028

Adherence to Mediterranean diet may thus reflect greater exposure to immunomodulating soil saphro-phytes giving protection against severe asthma.

KEY REFERENCES1. Hanski I, von Hertzen L, Fyhrquist

N, Koskinen K, Torppa K, Laatika-inen T, et al. Environmental bio-diversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci U S A 2012;109:8334-8339.

2. Prescott SL. Early-life environ-mental determinants of allergic diseases and the wider pandemic of inflammatory noncommunica-ble diseases. J Allergy Clin Immunol 2013;131:23-30.

3. Haahtela T, Malmberg P, Morei-ra A. Mechanisms of asthma in Olympic athletes--practical impli-cations. Allergy 2008;63:685-694.

4. Silva AC, Vieira RP, Nisiyama M, Santos AB, Perini A, Mauad T, et al. Exercise inhibits allergic lung inflammation. Int J Sports Med 2012;33:402-409.

5. Moreira A, Delgado L, Haahtela T, Fonseca J, Moreira P, Lopes C et al. Physical training does not increase allergic inflammation in asthmatic children. Eur Respir J 2008;32:1570-1575.

6. Barros R, Moreira A, Fonseca J, de Oliveira JF, Delgado L, Cas-tel-Branco MG, et al. Adherence to the Mediterranean diet and fresh fruit intake are associated with improved asthma control. Al-lergy 2008;63:917-923.


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• Individual measures for prevention and control of asthma should be among the priorities of the health professionals

• Optimal management should involve a network of care in which a well instructed and implicated patient plays a key role

• Very few interventions proved effective for asthma prevention• Individualised asthma control plans should be reinforced

Asthma is a chronic, sometimes lifelong condition, needing optimal adherence to best asthma care. In order to optimize the management of the asthmatic patient, individual prevention and control should be among the priorities of the health professionals (Figure 1).

Asthma prevention will mostly fo-cus on nutritional and environmen-tal interventions.

• Primary prevention addresses measures preventing asthma to occur, mostly in individuals with an increased susceptibility to develop the disease. Interven-tion trials have mostly focused on diets avoiding allergenic foods during pregnancy, breast-feed-ing, as well as on the delayed in-troduction of solid and/or aller-genic foods into the child’s diet. Overall, such measures have been proven to be ineffective in most groups of patients. Sim-ilarly, interventions leading to reduced allergen loads in the en-vironment (e.g. dust mite avoid-ance measures) of children at risk for asthma have been prov-en mostly ineffective.

• Secondary prevention address-es measures preventing the pro-gression of the disease. A few interventions have been suc-

cessful in some studies. A large multicenter interventional trial testing 18 months treatment with oral anti-histamine (ceti-rizine) has shown a preventing effect on asthma development in children with atopic eczema already sensitized to dust mites or grass pollens. A smaller tri-al with oral chromoglycate has shown the same effect. Disease progression from grass-pollen allergic rhinitis to allergic asth-ma has been prevented in part in a group of children undergoing sub-cutaneous allergen specific immunotherapy. This effect has been lasting for up to 10 years after immunotherapy.

• Tertiary prevention focuses mostly on optimal therapeutic management of the disease and is addressed elsewhere in the Global Atlas.

Asthma control at the individual level is mostly related at translat-ing the most recent therapeutic guidelines to the patient’s daily life.

Asthma control in children is close-ly linked to the social environment of the child. Daycare and school caregivers need to be aware of the child’s triggers for asthma (e.g. pet exposure), and adapt activities in order to avoid them. In addition to the parents, adults in charge of the child need to be instructed to recognize the first signs of asthma, and how to treat an asthma attack.

Asthma control in adolescents and adults is based on the individu-al’s responsibility to avoid poten-tial triggers and to self-treat first symptoms of asthma. Measuring peak flow expiratory rates may help to assess the degree of lung obstruction by the patient himself and to institute the initial “emer-

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AND CONTROL11

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gency treatment”. Measuring nitric oxide at the doctor’s office might provide guidance for assessing dis-ease control.

In conclusion, asthma prevention will always need physician supervi-sion, but optimal care will also need to involve a network of care, in which a well instructed and impli-cated patient plays a the key role.

KEY REFERENCES1. Maas T, Kaper J, Sheikh A, Knot-

tnerus JA, Wesseling G, Dom-peling E, et al. Mono and mul-tifaceted inhalant and/or food allergen reduction interventions

for preventing asthma in children at high risk of developing asth-ma. Cochrane Database Syst Rev 2009;(3):CD006480.

2. Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, place-bo-controlled trial: first results of ETAC. Early Treatment of the At-opic Child. Pediatr Allergy Immunol 1998;9:116-124.

3. Iikura Y, Naspitz CK, Mikawa H, Talaricoficho S, Baba M, Sole D, et al. Prevention of asthma by ketoti-fen in infants with atopic dermati-tis. Ann Allergy 1992;68:233-236.

4. Jacobsen L, Niggemann B, Dreborg

S, Ferdousi HA, Halken S, Høst A, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asth-ma: 10-year follow-up on the PAT study. Allergy 2007;62:943-948.

5. Gupta S, Wan FT, Hall SE, Straus SE. An asthma action plan created by physician, educator and patient online collaboration with usabili-ty and visual design optimization. Respiration 2012;84:406-415.

6. Sleath BL, Carpenter DM, Sayner R, Ayala GX, Williams D, Davis S, et al. Child and caregiver involve-ment and shared decision-making during asthma pediatric visits. J Asthma 2011;48:1022-1031.

Healthcare professionals

(doctors, nurses)

Environment

(work and leisure)

Assume responsibility for

self-management

Understand my disease

Integrate into

the Network of care Family, friends

Patient’s organisations

Figure 1 Essential steps towards an individualised asthma treatment plan.

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• Asthma is extremely common• It is amenable to treatment• Correct diagnosis is critical• Appropriate treatment prevents morbidity and mortality• Patient education and instruction on monitoring to aid self

management are essential components of disease management• Inhaler technique is of paramount importance• Access to structured care and appropriate medication must

become health care priorities• If control cannot be achieved in the primary care setting onward

referral for further evaluation is highly recommended

Asthma imposes a significant dis-ease burden to individuals and health economies. Evidence sug-gests that a substantial number of patients are not controlled according to accepted parame-ters, although the level of control achieved is somewhat dependent on the instrument used to measure it. There is a pressing need to un-derstand the level of control that could be achieved in primary care and a further need to understand the barriers to achieving this.

In many nations the first point of contact for many diseases is the general practitioner (GP) or family practitioner although this service may equally be provided by emer-gency rooms or specialists working in the primary care environment.

Although to date there is no effec-tive primary preventative strategy to prevent the occurrence of asth-ma, we are fortunate to have many resources at our disposal to detect and make early interventions prior to significant lung damage occur-ring and to reduce the impact of the disease on quality of life by re-storing lung function and reducing rates of complications (exacerba-tions, hospitalisations and death).

Although the incidence of asthma appears to have peaked and may be

falling in higher prevalence coun-tries it is very much on the increase in lower prevalence countries as life style and culture evolves (Fig-ure 1).

The first role of Primary Care (PC) is to detect, in those presenting with symptoms, and make a diag-nosis of asthma. The role of histo-ry taking is paramount but the use of simple diagnostic tests such as peak flow readings demonstrating variability or marked diurnal vari-ation are helpful; spirometry with reversibility is the more favoured approach but is frequently not available; an elevated peripheral eosinophil count helps to support a diagnosis as does the presence

of atopy. Bronchoprovocation testing has previously only been available in the hospital setting but new technologies such as manni-tol challenge have the potential to allow this also to occur in the com-munity setting. Guidelines may be helpful in determining the likeli-hood of a collection of signs and symptoms being representative of asthma (Table 1).

In terms of assessment of both se-verity and control, simple instru-ments such as the Royal College of Physicians Three questions, Asth-ma Control Test or Asthma Control Questionnaire are available. These give an indication of disease seve-rity and are responsive to change

THE ROLE OF PRIMARY CARE IN THE PREVENTION AND

CONTROL OF ASTHMA12

Ke y m e ssag e s

Dermot Ryan Woodbrook Medical Centre

Loughborough, UK

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1950

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High prevalence country

Intermediateprevalence country

Low prevalence country

1960 1970 1980 1990 2000

Figure 1 Incidence of asthma in high, intermediate in low prevalence countries. (Reproduced from Bousquet J, Bousquet PJ, Godard P, et al. The public health

implications of asthma. Bull World Health Organ 2005;83:548-54.)

as control is achieved. This assess-ment may be supplemented by evi-dence of peak flow variability, need for rescue inhalers or, potentially, exhaled nitric oxide, the role of which has yet to be clarified.

Once the diagnosis has been made the next task is to manage the disease in collaboration with the patient. A discussion with the pa-tient as to what asthma is and what treatments and lifestyle modifi-cations (such as smoking cessa-tion) are necessary to help abolish symptoms and normalize life is of great importance.

A crucial factor in patient educa-tion is teaching patients how and when to use their inhaler (Figure 2). This is not as easy as it might first appear, as many clinicians, whether in the community or hospitals, do not themselves know how to use commonly used inhalers rendering them unable to teach or check in-haler technique. There is an urgent need to rectify this situation. Gi-raud eloquently demonstrated that the greater the number of errors in technique, the lower the likeli-hood of achieving asthma control. Molimard demonstrated that poor technique is encountered with virtually all inhaler devices, each of which have a number of critical success factors (Figure 3). Training of patients in inhaler technique can result in sustained benefit.

TABLE 1

The likelihood of signs and symptoms being representative of asthma *

Features increasing the likelihood of asthma

• More than one of the following clinical symptoms: wheeze, breathlessness, chest tightness and cough particularly:

� Worse at night or early morning

� Symptoms in response to exercise, allergen exposure, cold air

� Symptoms after taking aspirin or β blockers

• History of atopic disorder

• Family history of asthma/atopic disorder

• Widespread wheeze heard on auscultation of the chest

• Otherwise unexplained low FEV1 or PEF ( historical or serial readings)

• Otherwise unexplained blood eosinophilia

Features that lower the probability of asthma

• Prominent dizziness, light headedness or peripheral tingling

• Chronic productive cough in the absence of wheeze or breathlessness

• Repeatedly normal examination of the chest when symptomatic

• Voice disturbance

• Symptoms with colds only

• Significant smoking history (i.e. > 20 pack years)

• Cardiac disease

• Normal PEF or spirometry when symptomatic. A normal spirogram/spirom-etry when not symptomatic does not exclude the diagnosis of asthma. Repeated measurements of lung function are often more informative than a single assess-ment.

* Reproduced from British Thoracic Society and Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma - A national clinical guideline, 2008, revised 2012

Figure 2 Which inhaler, how and when?

(© ruaidhri.ryan www.ruaidhri.co.uk)


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Figure 4 A centralised respiratory diagnostic service for primary care: a 4-year audit: 30% with a definite asthma and 11% with a suspected asthma. (Adapted

from Starren ES, Roberts NJ, Tahir M, et al. A centralised respiratory diagnostic service for primary care: a 4-year audit. Prim Care Respir J 2012;21:180-186.)

There is increasing evidence that many of those with a diagnosis of asthma and are not well controlled may have alternative diagnoses, as demonstrated in a study carried out in London which demonstrat-

ed that only one third of those re-ferred to a community respiratory assessment service with a definite diagnosis of asthma and only 11% of those with a diagnosis of proba-ble asthma actually had asthma.

Figure 3 Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. (Reproduced with permission of the European

Respiratory Society. Eur Respir J February 2002 19:246-251; doi:10.1183/09031936.02.00218402.)

Patients also need to know how to monitor their disease; recognizing and, if possible, avoiding identified triggers, having annual influenza vaccinations and attending for reg-ular structured reviews. They need to be aware of what symptoms or change in lung function (peak flow monitoring) may indicate a need to step up treatment or seek urgent medical attention.

The clinician also needs to com-mence appropriate medication regimes, informed by their nation-al guidelines. If failure to obtain control of symptoms occurs, rath-er than unquestioningly escalat-ing treatment, the clinician must launch a comprehensive struc-tured enquiry (Table 2) including the following items: smoking sta-tus; check inhaler technique; com-pliance with medication (checking against issues of prescriptions where possible); assess control using a validated instrument such as RCP three questions or Asthma Control Test evaluate the current treatment and assess whether it is adequate; enquire about co-mor-bidities in particular rhinitis, whether allergic or non allergic, lifestyle factors (diet, exercise, oc-cupation, hobbies, house moves). The attending physician has to ensure that the patient has a clear understanding of asthma and the medications needed to manage it and to provide ongoing support by frequent reviews (until control is achieved) and refer to national asthma charities web sites for fur-ther information.

Finally, the GP has to reconsider whether the diagnosis of asthma is correct; failure to gain control after reiteration of the steps enumerat-ed above suggests either an alter-native diagnosis or the need for re-ferral to a specialist in a refractory asthma clinic (Figure 4).

TABLE 2

Factors to be considered in a structured review

Smoking cessation psychological and pharmacological support

Inhaler technique regular assessment with demonstration devices

Monitoring symptom assessment ( RCP3 questions, ACT, ACQ)lung function : peak flow, spirometry

Pharmacology appropriate medications at appropriate doses

Life Style exercise, diet, obesity, employment, hobby

Education understanding asthma, medications used, self monitor-ing and self-management plan

Support follow up arrangements; contacts with patient groups

0 1 2 3 4 5 6 ≥7Number of errors

0

5

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uenc

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)

Frequency distribution of the number of errors in inhalation tech-nique (Left axis)

Relationship* be-tween number of errors and asthma instanility score (Right axis)

*Linear regression analysis r=0.3,

p < 0.0001.

GP referralDefinite Asthma

43

Asthma17

Restrictive9

Other9

No AirwayNarrowing

11

GP referralSuspected Asthma

99

Asthma11

Restrictive7

COPD2

No AirwayNarrowing

70

Other9

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Figure 5 Significant variability between individual practices in achieving asthma control.

Figure 6 Reduction in hospitalisations after an intervention to manage severe asthma. (Reproduced with permission of the European Respiratory Society.

Eur Respir J March 2010 35:515-521; published ahead of print July 30, 2009, doi:10.1183/09031936.00101009.)

Figure 7 Cost-effectiveness analysis of a state funded programme for control of severe asthma. (Reproduced from Franco R, Santos AC, do Nascimento HF, et al. Cost-effectiveness analysis of a state funded programme for control of severe asthma. BMC

Public Health 2007;7:82. Reprinted with permission under the Creative Commons Attribution License or equivalent.)

3500

3000

2500

2000

1500

1000

500

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A further challenge facing primary care is the significant variability in the standard of care delivered from country to country, region to region and practice to practice as

exemplified by the study illustrat-ed below (Figure 5) which demon-strates that in some practices just above 12% of patients had an ACQ score of 1.5 or above suggesting

poor control while in one practice just under 78% of patients had ACQ greater than 1.5%, with an average value of 36%. On the other hand this study gives an indication of what level of control it is possi-ble to achieve and suggests that in the majority of patients achieving control is a real possibility.

A further barrier to achieving good outcomes for patients with asth-ma is the provision of a structured health service coupled with access to appropriate medications. Work in Brazil has demonstrated very clearly that such an approach sig-nificantly reduces both morbidi-ty (Figure 6) and costs (Figure 7). Health care planners in different countries might wish to recognize this fact when allocating resources.

KEY REFERENCES1. Giraud V, Roche N. Misuse of cor-

ticosteroid metered-dose inhal-er is associated with decreased asthma stability. Eur Respir J 2002;19:246–251.

2. Mulloy E, Donaghy D, Quigley C, McNicholas WT. A one-year pro-spective audit of an asthma educa-tion programme in an out-patient setting. Ir Med J 1996;89:226-228.

3. Starren ES, Roberts NJ, Tahir M, O’Byrne L, Haffenden R, Patel IS, et al. A centralised respiratory di-agnostic service for primary care: a 4-year audit. Prim Care Respir J 2012;21:180-186.

4. Price D, Horne R, Ryan D, Free-man D, Lee A. Large variations in asthma control between UK general practices participating in the asthma control, concordance and tolerance initiative. Prim Care Respir J 2006;15:206.

5. Souza-Machado C, Souza-Machado A, Franco R, Ponte EV, Barreto ML, Rodrigues LC, et al. Rapid reduc-tion in hospitalisations after an in-tervention to manage severe asth-ma. Eur Respir J 2010;35:515-521.


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• A strategic partnership for improving asthma care involves patient representatives, healthcare professionals and policymakers

• As multi-service advocacy organizations, asthma patient groups around the world coordinate action, awareness and research projects concerning asthma care, prevention and research and advocate patient centered healthcare through partaking in government asthma policy formulation

• Several initiatives like EFA’s four year programme on allergy and pilot training for national programme development proved that patient groups can act as the key initiators for better priority, organization of care and collaboration in asthma

The role of asthma patient organi-zations is to support patients man-age their everyday life and advo-cate patient centered healthcare, environment and research poli-cies and practices. Most patients also have allergy on their agenda, which make activities comprehen-sive considering the link between several allergic diseases and asth-ma. Patient organizations are key partners for those working in asth-ma control and prevention. Asth-ma patient groups evolved from support groups into advocates for patient rights. The journey of pa-tient groups globally has similar features; there is a need to meet other patients to share experienc-es and tips to manage with asthma in daily life, access information as well as education on asthma tar-geted and adjusted for patients, as for example, in the case of a family with a newly diagnosed asthmatic child. These are crucial traditional roles of patient organisations. The partnership between healthcare professionals and patient organisa-tions is present from the beginning as there is a need for their medical expertise in their activities.

Development of asthma patient groups depends on the stage of a civil society’s development in a

particular country and the avail-abity of resources. Asthma patient groups around the world have de-veloped or are on their way to de-velop into multi-service advocacy organisations. Apart from the tra-ditional patient group activities, they coordinate action, awareness and research projects concern-ing asthma care, prevention, risk factors and research; advocate through partaking in government asthma policy formulation; support research or provide patient per-spective in research projects; and develop tools for improved asthma management (Figure 1).

The European Federation of Aller-gy and Airways Diseases Patients’

Associations (EFA) represents peo-ple with allergy, asthma and chron-ic obstructive pulmonary disease at the European level, supporting development of national plans on allergy/asthma, advocating at EU institutions, and influencing EU health, environment and research policies. For example, the frame-work for air pollution and tobacco control legislation occurs at the EU level, while EU funds research and the European Medicines Agency evaluates medicines and their in-formation and coordinates Phar-macovigilance. EFA’s job is to en-sure patient’s perspective in each of these. EFA’s 4 year programme on allergy supports the develop-ment of and political priority for

ROLE OF PATIENT ORGANISATIONS IN THE CONTROL AND

PREVENTION OF ASTHMA13

Ke y m e ssag e s

Breda Flood European Federation of Allergy and

Airways Diseases Patients’ Associations

Georg Schäppi aha! Swiss Allergy Center

Bern, Switzerland

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national programmes on allergy/asthma, highlighting the current National Allergy Programme and a former on Asthma in Finland. EFA organized a pilot training for national programme development with delegations from three coun-tries (Bulgaria, Norway, Italy). The delegations gathered key stake-holders: patient representatives, healthcare professionals and pol-icymakers. Patient groups can act as the key initiators for higher pri-ority, organization of care and col-laboration in asthma. (Figure 2).

Asthma patient groups are organ-ized from local to national level, from national to regional (like EFA) and now most recently at global level through Global Asthma and Allergy Patient Platform (GAAPP), founded in 2009. Like access to es-sential asthma control and preven-tion, disparities exist in the organi-

zation capacities of patient groups, and therefore their services and advocacy in the world. A global support for the development of such groups is in the interest of pa-tients and all those interested and involved in asthma.

KEY REFERENCES1. Valovirta E, editor. EFA Book

on Respiratory Allergies. Raise Awareness, Relieve the Burden. 2011.

2. Fighting for Breath – A Europe-an Patient Perspective on Severe Asthma. http://www.efanet.org/wp-content/uploads/2012/07/Fighting_For_Breath1.pdf, ac-cessed May 20, 2013.

3. Papadopoulos NG, Agache I, Bavbek S, Bilo BM, Braido F, Car-dona V, et al. Research needs in al-lergy: an EAACI position paper, in collaboration with EFA. Clin Transl Allergy. 2012;2:21.

Figure 1 Issues for people with asthma.

Figure 2 Patients participation in the European Parliament.

My treatment

Researchin

Myparticipation

My Environment

• Prevention• Smoking cessation• Exercise, nutrition• Early diagnosis• Health care• Social support• Food labelling• Medical devices• Co-morbidities

• Medicines• Rehabilitation• Reimbursement• Patient information• Patient education• Education• Adherence, concordance• ICT, eHealth

• Treatment• Society• Health • Environment &

Research Policy

• Quality of Life• Finding the cure

• Prevention• Care• Medicines

• Indoor Air• Outdoor Air• Chemicals

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aha! Center for Allergy Switzerland

Allergy India

Allergy New Zealand Inc

Anaphylaxis Australia Inc

Anaphylaxis Canada

Anoiksi NGO Asociacion espanola de alergicos a alimentos y latex

Association Francaise pour la Prevention des Allergie

(AFPRAL)

Deutscher Allergie und Asthmabund eV

European Federation of Allergy & Airway Diseases

Patients Association

Food Allergy Research & Education

Food Allergy Italia

Fundacion Creciendo con Alergias Alimenarias

Swedish Asthma and Allergy Association

The Allergy Society of South Africa

S.O.S Alergia

EAACI PATIENT ORGANISATIONS COMMITTEE

Anaphylaxis Ireland

Association québécoise des allergies alimentaires

Prevention des Allergies A.S.B.L.

The Hong Kong Allergy Association

Yahel Food Allergy Network Israel

The European Anaphylaxis Taskforce CV

The Anaphylaxis Campaign UK

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a • Asthma is a public health issue and needs a community-based solution. The first step is to involve all the key stakeholders

• Asthma exacerbations can be proactively prevented by improving disease control with the help of guided self-management

• With a nationwide multidisciplinary and comprehensive public health programme the burden of asthma and allergies on individuals and society can be decreased

• Networking of allergy experts with primary care and pharmacists is the key for effective implementation of a national public health programme

• Non-governmental organizations (patient associations) in collaboration with healthcare professionals are in a key position to inform and educate the general public

• The European Federation of Allergy and Airways Diseases Patients’ Associations has started a 4-year Awareness Programme on Respiratory Allergies calling upon European policy makers to develop a strategic approach to asthma and respiratory allergies

We need goal-orientation in the prevention and control of asthma. The only way to make changes hap-pen is the social process, in which the attitudes of the population in-fluence the decision making. Com-prehensive social actions, activities and collaboration should be added to the concrete work for decreas-ing health risks.

The basis for an effective socie-ty input is to make changes in the whole society instead of only car-ing for patients or for those at high risk. When starting a national pub-lic health programme a practical plan for implementation is needed, in addition to clearly defined and measurable goals.

From the health care point of view it is important to allocate resourc-es not only for the patients but also for public health actions, including preventative measures and life style changes. Good quality air, reg-ular exercise, balanced diet, weight control and non-smoking are im-portant for all chronic diseases.

ASTHMA AS A PUBLIC HEALTH PROBLEMAsthma is a major global public health problem. The prevalence of asthma continues to rise in many countries: the current estimate of

300 million asthmatics worldwide is expected to increase with 33% by 2025. Every year 250 000 peo-ple die prematurely due to asth-ma. In Europe the prevalence of the doctor-diagnosed asthma in children is around 5% and slightly lower in adults. However, asthma symptoms in the general popula-tion occur at a three times higher rate, suggesting a considerable percentage of under diagnosis. Occupational asthma accounts for 15% of all occupational diag-

noses. The annual costs of asthma in Europe are estimated at 18 bil-lion Euro. The rising prevalence of asthma and of other respiratory al-lergies, the increased use of health services, emergency room visits, hospitalizations and medication costs poses a major socioeconomic burden on national and European budgets. Asthma leads to billions of days of lost productivity through absenteeism or presenteeism with costs estimated for Europe at ap-proximately 10 billion Euro annu-

SOCIAL MOBILIZATION FOR PREVENTION AND CONTROL

OF ASTHMA 14

Ke y m e ssag e s

Erkka Valovirta University of Turku

Finland

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ally. In addition to the economic burden, physical, emotional, and social effects of asthma negatively impact the quality of life of patients and their families. Asthma is relat-ed to considerable absenteeism from school.

It is generally considered that the majority of patients with asthma can be sufficiently controlled using adequate treatments and a struc-tured follow-up system. However, there are limitations in controlling patients with severe asthma who suffer from ongoing symptoms and have frequent exacerbations with emergency room visits and hospi-talizations and reduced quality of life despite receiving the best avail-able treatment. This group repre-sents about 10% of all asthma pa-tients and accounts for more than 75% of the overall asthma cost. In addition, even patients with mild to moderate asthma may have ex-acerbations adding to increased costs and to decreased quality of life.

SOCIAL MOBILIZATION FOR PREVENTION AND CONTROL OF ASTHMAWhen asthma is controlled, most of the patients with mild and mod-erate asthma can live a normal life. Health care resources should be used more targeted and tailored to the patients with severe asthma or with frequent exacerbations. Asthma exacerbations can be pre-vented proactively by improving disease control using a guided self-management action plan.

National public health pro-grammes decreasing the burden of asthma can be best exemplified by the Finnish Asthma Programme 1994-2004, the Czech Initiative for Asthma and the Finnish Allergy Programme 2008-2018.

In Finland, the burden of asthma was significantly reduced since early 90´s when the National Asthma Programme was initiated. The Finnish Asthma Programme focused on early treatment of bronchial inflammation (“hit early, hit hard”), networking and guid-ed-self-management. The key tools were education of primary health-care professionals, networking of primary and specialized care with pharmacies and patient organi-zations and the guided self-man-agement plan to prevent and/or promptly treat asthma exacerba-tions. With these tools asthma pa-tients have better control, less ex-acerbations, less school and work absenteeism, less retirement. And, less costs to the society and to the patient, even if at the same time the number of patients on regular asthma medication has increased.

The Czech Initiative for Asthma has also proven to be effective in improving the quality of life for pa-tients and reducing costs despite the increasing number of asthma patients on regular treatment.

The Finnish National Allergy Pro-gramme 2008-2018 is focusing on prevention, tolerance induction, quality control of the diagnostic work-up and early treatment of exacerbations. New body of evi-dence for tolerance induction and national consensus gathering all relevant stakeholders are the foundation for this public health programme. The tools are far much the same as in the Asthma Programme, with educa-tion the key element. The knowledge accumulated from the asthma guided self-management in adults is being used in the Allergy Programme for children with asthma, allergic rhi-

noconjunctivitis, atopic dermatitis, food allergy and anaphylaxis. The key messages (Table 1) were tak-en very positively by the health-care professionals and the general population. The Educational pro-gramme was a great success with quite limited man power. By the end of the year 2012 the Finnish Lung Health Association organ-ized with one specialist, working half day in collaboration with local key opinion leaders and one full-time Project Nurse 175 multidis-ciplinary educational meetings with almost 11000 health care professionals participating: 25% physicians, 50% nurses, 10% phar-macists, 15% dieticians, students and others (Table 2). The topics of the meetings were targeted to the Goals of the Programme and tailored to local needs. Education-al meetings were free of charge and organised during the working hours inside or nearby the health-care unit (University/Central/Local Hospitals and Health Care Cen-tres).

In 2011 three non-governmental organizations (Allergy and Asthma Federation, Pulmonary Associa-tion and Skin Federation), started a comprehensive information and communication campaign. This 4-year project implements the new recommendations among allergic people and general population. The main tools are the internet via

TABLE 1

The key messages of the Finnish Allergy Programme 2008-2018

• Endorse health, not allergy

• Strengthen tolerance

• Adopt a new attitude to allergy

� Avoid allergens only if mandatory

• Recognize and treat severe allergies early

� Prevent exacerbations and attacks

• Improve air quality. Stop smoking!

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TABLE 2

Educational process of the implementation of the Finnish Allergy Programme to the health care

Themes 2008 2009 2010 2011 2012 Total

Programme LaunchCentral Hospitals

16 10 - -26 events

1585 participants

Food AllergyPrimary Care

7 29 25 8 -69 events

2253 participants

Allergy Health Central Hospital districts

- 3 10 11 -24 events

2293 participants

AnaphylaxisPrimary Care

- - 1 16 1431 events

2174 participants

Allergy-healthy Child Central Hospital districts

- - - - 88 events

675 participants

More tolerance – less allergyCentral Hospital districts

- - - - 99 events

690 participants

Northern LaplandMilitary Forces etc

- - 1 1 68 events

442 participants

All 26.11.2012 23 42 37 36 37175 events

>10 000 participants

the homepages of the project and seminars for media reporters. In addition other methods of mod-ern media are used. Two half-time workers are managing the Project. They gave in 2011 and 2012 38 talks all over the country and 20 Radio and TV interviews. All three NGOs communicate on every day basis different topics of the Finn-ish Allergy Programme. The first results of the Finnish Allergy Pro-gramme indicate that allergy bur-den can be reduced with relatively simple means.

EUROPEAN AWARENESS PROJECT OF RESPIRATORY ALLERGIESOn European level, the European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) has started in 2011 a 4-year Awareness Programme on Res-piratory Allergies – Raise Aware-ness, Relieve the Burden. The programme calls upon European policy makers, European Union and Member States to take the neces-

sary steps to develop a strategic, comprehensive and integrated ap-proach to asthma and respiratory allergies that brings all initiatives and actions under one umbrella, and to support the launch and im-plementation of national public health programmes.

EFA surveyed in 2011 its member associations in 18 European coun-tries to gain information about national asthma and respiratory allergy policies. The survey showed that the quality of life of patients has improved considerably in countries with a robust national programme, but not in countries where national programme either fails to involve all stakeholders (e.g. involving only specialists) or has difficulties in being implemented or sustained.

KEY REFERENCES1. Haahtela T, Tuomisto LE, Pietinal-

ho A, Klaukka T, Erhola M, Kaila M, et al. A 10 year asthma programme in Finland: major change for bet-ter. Thorax 2006;61:663-670.


3. Valovirta E, editor. EFA Book on Respiratory Allergies. Raise Awareness, Relieve the Burden. 2011.

4. Kauppi P, Linna M, Martikainen J, Mäkelä MJ, Haahtela T. Follow-up of the Finnish Asthma Programme 2000-2010: reduction of hospital burden needs risk group rethink-ing. Thorax 2013;68:292-293.


6. Haahtela T, Valovirta E, Kaup-pi P, Tommila E, Saarinen K, von Hertzen L, et al. The Finnish Al-lergy Programme 2008-2018 – scientific rationale and practical implementation. Asia Pac Allergy 2012;2:275-279.


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• Prevention and control of asthma need to be an integral part of the national strategy for prevention and control of noncommunicable diseases.

• Multisectorial public policies to reduce exposure to risk factors and address social determinants as well as health systems organized around the principle of universal health coverage are necessary for prevention and control of asthma.

• Scaling up efforts for prevention and control of asthma will contribute to the attainment of the voluntary global target of reducing premature mortality from noncommunicable diseases with 25% by 2025.

HEALTH AND ECONOMIC IMPACT OF ASTHMAChronic respiratory diseases, in-cluding asthma were responsible for 4.2 million deaths globally in 2008. Over the period 2011-2025, the cumulative lost output in low- and middle-income countries as-sociated with chronic respirato-ry diseases including asthma, is projected to be US$ 1.59 trillion (Table 1). Social determinants sig-nificantly influence the prevalence of asthma (Table 2). There are sub-stantial health and economic gains attached to prevention, early de-tection, adequate treatment and good control of asthma.

SUSTAINABLE SOLUTIONS Prevention and control of asthma need to be an integral part of the national strategy for prevention and control of noncommunicable diseases (NCDs). Public health pol-icies need to reduce the exposure of people to risk factors for asthma and mitigate social determinants that increase vulnerability to asth-ma. Tobacco smoke, allergens, air pollution including indoor air pol-lution from solid fuel combustion, poor housing, extreme weather conditions, all play a role in asthma and need to be addressed through multisectoral public policies.

In addition, effective control of asthma requires health system strengthening across all compo-nents: governance, health financ-ing, information, human resourc-es, service delivery and access to inexpensive good quality generic medicines and basic technologies. Health systems that have proven to be most effective in improving health and equity organize their services around the principle of universal health coverage and pro-mote actions at the primary care level. An integrated primary care programme, delivered by trained health workers, which provides equitable coverage and access to basic diagnostics and essential medicines (e.g. at least salbutamol

and inhaled beclometasone) is re-quired. World Health Organization (WHO) guidelines and tools are available for this purpose.

The 66th World Health Assem-bly endorsed the Global Action Plan for prevention and control of noncommunicable disease and the global monitoring framework to track progress in its implemen-tation. The monitoring framework includes nine voluntary global targets and 25 indicators. A 25% reduction in premature mortality from major NCDs by 2025 is one of the nine voluntary global targets. Scaling up efforts for prevention and control of asthma will contrib-ute to the attainment of this volun-

ASTHMA IN RESOURCE CONSTRAINED SETTINGS15

Ke y m e ssag e s

Shanthi Mendis World Health Organization

Geneva, Switzerland

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tary global target for reducing pre-mature mortality from NCDs.

KEY REFERENCES1. World Health Organization. Caus-

es of death 2008: data sources and methods, World Health Or-ganization, Geneva, 2011, http://www.who.int/healthinfo/global_burden_disease/cod_2008_sourc-es_methods.pdf, accessed May 20, 2013.

2. World Health Organization, World Economic Forum. From

burden to “best buys”: reducing the economic impact of non-com-municable diseases in low- and middle-income countries. World Health Organization and World Economic Forum, 2011, http://www.who.int/nmh/publications/best_buys_summary, accessed May 20, 2013.

3. Hosseinpoor AR, Bergen N, Men-dis S, Harper S, Verdes E, Kunst A, et al. Socioeconomic inequality in the prevalence of noncommunica-ble diseases in low- and middle-in-come countries: results from the

World Health Survey. BMC Public Health, 2012;12:474.

4. World Health Organization. Pack-age of essential noncommunica-ble (PEN) disease interventions for primary health care in low-re-source settings. Geneva: WHO Press, 2010.

5. World Health Organization. Pre-vention and control of noncom-municable diseases: Guidelines for primary health care in low resource settings. Geneva: WHO Press, 2012.

TABLE 1

Economic burden of noncommunicable diseases, 2011-2025 (US$ trillion in 2008)

Country income group

Cardiovascular diseases

CancerRespiratory

diseasesDiabetes Total

Upper-middle 2.52 1.20 1.09 0.31 5.12

Lower-middle 1.07 0.26 0.44 0.09 1.85

Low-income 0.17 0.05 0.06 0.02 0.31

Total of low- and middle-income

3.76 1.51 1.59 0.42 7.28

TABLE 2

Economic burden of noncommunicable diseases, 2011-2025 (US$ trillion in 2008) *

Middle income group Low income group

Men Women Men Women

No formal schooling

9.2 (7.7 - 10.8)

10.2 (9.0 - 11.4)

6.4 (5.7 - 7.1)

7.1 (6.5 - 7.7)

Less than primary school

6.8 (5.9 - 7.8)

9.7 (8.8 - 10.6)

5.7 (4.8 - 6.5)

5.7 (5.0 - 6.4)

Primary school completed

7.4 (6.5 - 8.2)

7.7 (6.7 - 8.6)

6.0 (5.0 - 6.9)

6.2 (5.2 - 7.2)

Secondary / high school completed

5.7 (5.1- 6.3)

6.2 (5.7 - 6.8)

4.6 (3.8 - 5.3)

5.5 (4.7 - 6.4)

College completed or above

4.2 (3.0 - 5.3)

3.9 (3.3 - 4.6)

3.7 (2.8 - 4.7)

3.1 (1.9 - 4.3)

* Data from Hosseinpoor AR, Bergen N, Mendis S, et al. Socioeconomic inequality in the prevalence of noncommunicable diseases in low- and middle-income countries: results from the World Health Survey. BMC Public Health, 2012;12:474

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• Prevention, early diagnosis and treatment of allergy and asthma is recognized as a priority for the EU’s public health policy and the United Nations

• Identifying the missing links in the process between setting-up a program for prevention and making it work is essential

• Focusing on pathomechanisms of asthma inflammation, identifying the factors increasing the risk of asthma exacerbations, the window of opportunity for a successful intervention and designing more effective anti-inflammatory drugs should go hand in hand with increasing networking with other specialists and healthcare professionals and patients organisations, educational programmes, increased social awareness and mobilisation of resources and a better definition of short, medium and long-term goals to impact morbidity in asthma and allergy

Asthma and allergic diseases start early in life and persist throughout life. They could also appear later, at any time for reasons we still do not understand. Many of the develop-ing countries are facing a rapid in-crease in prevalence, disability and costs. In some countries the asthma and allergy epidemic may be leve-ling off, but the morbidity will stay high. They are indeed major chron-ic respiratory diseases, for which prevention, early diagnosis and treatment is recognized as a prior-ity for the EU’s public health policy and the United Nations (High Lev-el meeting on Non-Communicable Diseases, 2011). Given that allergy triggers, including rapid urbaniza-tion, pollution and climate change, infections are not expected to change in the foreseeable future, it is imperative that steps are tak-en to develop, strengthen and op-timize preventive and treatment strategies. However, we are still uncertain how to prevent children from developing asthma and aller-gic diseases.

Very few prevention programs have been successful so far: aller-gen avoidance, pharmacothera-py, allergen immunotherapy, food diet and pre/probiotics, education campaigns. The Finnish Asthma

Programme (FAS-P: 1994-2004), extended to 7 countries (Brazil, Chile, China-Hong Kong, Ireland, Japan, Poland, Singapore), appears to have been the most effective, showing a cost-effective reduction of asthma burden but not asthma prevalence over time. The Finnish Allergy Programme (FAL-P, 2008-2018) is currently implemented in the country and a reduction of the allergy epidemic is expected. High oral dose of food allergens in early infancy may promote the develop-ment of immunological tolerance. Allergen immunotherapy is the only currently available medical

intervention that has the potential to affect the natural course of the disease. What does work and not work should be listed and reanal-yzed carefully. The missing links in the process between setting-up a program for prevention and mak-ing it work is labeled as “implemen-tation gap”.

In order to understand why some interventions and/or programs are working, while others have not met expectations, the common factors that stood out prior to successful implementations by examining the “implementation gap” are listed be-low:

DEALING WITH THE IMPLEMENTATION GAP FOR ASTHMA PREVENTION AND

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Pascal Demoly University Hospital of Montpellier

France

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• Understanding better the pa-tho mechanisms of asthma in-flammation; for example, impor-tant advances in our knowledge of genetic associations with allergic disease, have not clari-fied the underlying pathological pathways, probably because we have yet to understand their in-teractions with environmental exposures. We also lack know-ledge on epigenetic mecha-nisms, now thought to be impor-tant in asthma and allergies

• Including scientists from other disciplines to better appraise the role of our environment in the epidemics

• Identifying the factors increas-ing the risk of asthma exacer-bations (with a special focus on viruses, allergens and patient behaviors)

• Identifying the best window (age group) for intervention (de-pending on the aim: primary vs secondary/tertiary prevention)

• Having short-term goals to im-pact morbidity (emergency,

hospitalization rate, mortality, disability) and long-term goals to decrease the incidence

• Designing more effective an-ti-inflammatory drugs / drug combinations and educational programs that maintain control of the diseases and novel treat-ments such as innovative immu-nological interventions that pre-vent asthma and allergies

• Combining both asthma and al-lergy plans

KEY REFERENCES 1. World Health Organization, Fact

Sheet n°307, 2011, http://www.who.int/mediacentre/factsheets/fs307/en/index.html, accessed May 20, 2013.

2. Bousquet J, Khaltaev N, editors. Global surveillance, prevention and control of chronic respira-tory diseases: a comprehensive approach. Geneva: WHO Press, 2007.

3. Samoliński B, Fronczak A, Włodarczyk A, Bousquet J. Council of the European Union conclusions on chronic respira-tory diseases in children. Lancet

2012;379:e45-46.

4. Beaglehole R, Bonita R, Alleyne G, Horton R, Li L, Lincoln P, et al. UN High-Level Meeting on Non-Communicable Diseases: addressing four questions. Lancet 2011;378:449-455.


6. Haahtela T, Tuomisto LE, Pietinal-ho A, Klaukka T, Erhola M, Kaila M, et al. A 10 year asthma programme in Finland: major change for bet-ter. Thorax 2006;61:663-670.


8. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121:1331-1336.

9. Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K, Laatika-inen T, et al. Environmental bio-diversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci USA 2012;109:8334-8339.

Ideas

Structured projects

Invest in research

Extended networking

Critical appraisal of impact

Understand better the pathomechanisms of asthma

More efficient drugs

Holistic approach to asthma (environment, society,

economy)

Short and long-term goals

Barriers to implementation

Asthma prevention and control

Figure 1 Dealing with the implementation gap for efficient asthma prevention and control.

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• Generating resources for prevention and control of asthma is a difficult issue requiring constant political work at national and international levels

• There are no asthma programs sponsored by the World Health Organisation

• In the European Union most of the basic funding for research and health programs comes from local financial commitments in individual EU countries

• The European Commission announces competitions: in science - DG RESEARCH, in public health - DG SANCO, in innovation and competitiveness - DG CNECT, and others

Information on best practices on measures for prevention and con-trol of chronic diseases can be obtained through local or inter-national sponsorship programs. In both cases, political decisions are fundamental. The global initiative highlights the key role of the World Health Organisation (WHO). The health policy is decided in the UN general assembly resolution which is preceded by a number of previ-ous discussions and negotiations carried out at regional and global level in the WHO. The funds that the WHO receives from member-ship fees are not enough to con-duct international programs. Usu-ally the additional support comes from private sponsors such as the Bloomberg Foundation, which es-tablished programs dedicated to the fight against smoking. There are no programs sponsored by the WHO for asthma.

In the European Union (EU), ac-cording to article 168 of the Treaty on the Functioning of the European Union, a high level of human health protection shall be ensured in the definition and implementation of all Union policies and activities. In this context, the role of the promo-tion of human health by the Euro-pean institutions is very important,

particularly the Commission (EC) should also take into account the role of the National Contact Points during the consultations in the pro-cedures for the elaboration of pro-grammes. The subject should be promoted not only by interested stakeholders but also by national authorities. Actions at all levels of this complex network are needed to guarantee its translation into different European programmes and into the subsequent themes of calls for proposals. However, most of the basic funding for research and health programs comes from local financial commitments in in-dividual EU countries. The inter-nal politics of each country deter-mines national priorities, resulting

from the specific health status of the population. The transfer of these problems to the internation-al forum is usually the result of an agreement between countries and is usually realized by the presiden-cy of the council of the EU done by particular Member States (MS). The 27 EU Ministries of Health adopt conclusions on priorities on the basis of which the EC prepares specific programs and associated funding. For asthma, the Polish Presidency put forward the initi-ative “Conclusion of EU Council on chronic respiratory diseases in children” . Following this conclu-sion the Commission can includ this issue in different programs, ex. in science - DG RESEARCH, in

GENERATING RESOURCES FOR PREVENTION AND CONTROL

OF ASTHMA17

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Bolesław Samoliński Medical University of Warsaw

Poland

Agnieszka Czupryniak Expert in European Programmes and

Healthcare, Warsaw, Poland

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public health - DG SANCO, in inno-vation and competitiveness – DG CNECT, and others, e.g. Ambient Assisted Lining (AAL). (Table 1). One of the distinguishing features of the conclusions adopted during the Polish Presidency was to sup-port networks such as GA2LEN and GARD, which promote asthma policy based on scientific grounds. Thanks to the follow-on efforts of the Cyprus Presidency chronic respiratory diseases should be im-plemented into EU health policy as “the links between early life events and healthy ageing using inter alia longitudinal studies” as reflected in the conclusions section. Conse-quently, EU institutions gave rise to the support for further efforts to prevent and control asthma.

In conclusion, it should be noted

that raising funds for prevention and control of asthma is a diffi-cult issue requiring constant po-litical work at all levels: national and international, including polit-ical lobbying, which aims to raise awareness among politicians and policymakers of the importance of the respiratory health of current and future generations.

KEY REFERENCES1. Treaty on the functioning of the

European Union. Article 168.

2. Samoliński B, Fronczak A, Kuna P, Akdis CA, Anto JM, Bialoszewski AZ, et al. Prevention and control of childhood asthma and allergy in the EU from the public health point of view: Polish Presidency of the European Union. Allergy 2012;67:726-731.

3. Samoliński B, Fronczak A,

Włodarczyk A, Bousquet J. Council of the European Union conclusions on chronic respira-tory diseases in children. Lancet 2012;379:e45-46.

4. Council of the European Union. Council conclusions on preven-tion, early diagnosis and treat-ment of chronic respiratory dis-eases in children. 2011: http://www.consilium.europa.eu/ue-docs/cms_Data/docs/pressdata/en/lsa/126522.pdf, accessed May 20, 2013.

5. Council of the European Union. Council conclusions on Healthy Ageing across the Lifecycle, 3206th EMPLOYMENT, SOCIAL POLICY, HEALTH and CONSUM-ER AFFAIRS, Council meeting. 2012: http://www.consilium.eu-ropa.eu/uedocs/cms_data/docs/pressdata/en/lsa/134097.pdf, ac-cessed May 20, 2013.

TABLE 1

EU resources for prevention and control of asthma

Institution Programe Website *

EC DG RE-SEARCH

FP7 and from 2014 – Horizon 2020

� http://cordis.europa.eu/fp7/dc/index.cfm � http://ec.europa.eu/research/participants/portal/page/fp7_calls

EC DG SANCO, Public Health Programme � http://ec.europa.eu/health/programme/policy/index_en.htm � http://ec.europa.eu/health/programme/how_does_it_work/call_for_proposals/index_en.htm

EC DG CNECT Competitiveness and innovation –ICT Policy Support Programme (ICT PSP)

� http://ec.europa.eu/digital-agenda/en/ict-policy-support-pro-gramme � https://ec.europa.eu/digital-agenda/sites/digital-agenda/files/cip_ict_psp_wp2013_publication.pdf

European Commission

The European Innovation Partner-ship on Active and Healthy Ageing

� http://ec.europa.eu/research/innovation-union/index_en.cfm? section=active-healthy-ageing � http://ec.europa.eu/social/main.jsp?langId=en&catId=89 &newsId=1065&furtherNews=yes

Ambient Assisted Lining

Ambient Assisted Lining Joint Programme -ICT for ageing well

� http://www.aal-europe.eu

*accessed May 20, 2013

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• Asthma treatment has improved with the development of guidelines

• The effectiveness of asthma treatment can be assessed by monitoring measures of disease control

• The next major advance to significantly reduce the burden of asthma is the development of approaches to prevent this disease

Over the past three decades, there have been amazing advances to more fully understand the mech-anisms of asthma, risk factors as-sociated in its development, and identification of safe and effective treatment approaches to control this disease. As a consequence, the significant morbidity associated with asthma has improved, but not disappeared.

To achieve goals of improved asth-ma care, guidelines for its diagno-sis, treatment and management were developed. Asthma guide-lines provide physicians, health care providers, and patients with an evidence-based approach to treatment and goals to measure the effectiveness of these under-

takings. Central to the effective management of asthma is dis-ease control. The effectiveness of asthma control can be defined by assessments made in two major domains: impairment and risks (Ta-ble 1). Impairment assesses the pa-tient’s symptoms, need for rescue treatment, interference with daily activities, and lung function. With treatment based upon the under-lying severity of asthma, it is antic-ipated that markers of impairment can be reduced and sustained. Markers of impairment largely re-fer to the “here and now” aspects of asthma that patients experience on a day-to-day basis. In addition, effective control of asthma needs to include assessments of future risks. Future risks include exacer-bations, progressive loss of lung function, and side-effects from medication. Therefore, effective and comprehensive management

must include control of both com-ponents of asthma, impairment and risks. Guidelines for the care of asthma have helped us achieve success in the control of asthma and by this to reduce the burden of this disease.

Despite these advances, asthma continues to impart a huge level of morbidity to patients with this disease, to families of the affected, and to society because of the asso-ciated costs. In the United States, for example, the burden of asthma is huge. Nearly 25 million patients in the United States have asthma. The prevalence of asthma is felt in patients of all ages with morbidity highly variable – mild disease with infrequent symptoms to patients who experience daily compromis-es to their lifestyle and have lim-ited responses to treatment. In the United States, the economic

ASTHMA PREVENTION AND CONTROL: WHY IT SHOULD NOT

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William W. Busse University of Wisconsin

USA

TABLE 1

Assessment of asthma control

Impairment

• Symptoms (day and night)

• Need for rescue treatment

• Limitation of daily activities

• Lung functions

Risks

• Exacerbations

• Progressive loss of lung function

• Side effects from medication

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burden of asthma is also high with annual costs in the range of $18 billion. These costs include direct expenses for care, medication, and, when necessary, hospitalizations. Indirect costs also contribute a sig-nificant portion of this burden and arise from loss of work, absence from school, and family expenses associated with the need to pro-vide care for affected family mem-bers.

Treatments for asthma are contin-ually improving and hold the prom-ise for greater specificity towards the underlying disease; however, these are treatments for those al-ready affected and afflicted with asthma. To truly have an impact on asthma and to reduce the burden of this disease, it is critical now to move forward and develop meth-ods to prevent asthma. How close are we to this critical goal?

The development of asthma is in-fluenced by many factors, many of which are interactive with one an-other. Asthma has its roots in the genetics of an individual patient as a family history for this disease is a major risk factor. For the disease to develop, however, other influences need to occur and by this create a ‘gene-by-environment’ interaction. In this regard, a number of key ob-

servations have been made. First, allergic sensitization appears, at least for children, to be a major risk factor in the development and ex-pression of asthma. Allergic sensi-tization, however, by itself may not lead to asthma and other factors need to be considered. Evidence has shown that respiratory infec-tions, primarily viral respiratory infections, are key to the develop-ment of asthma. Some bacterial in-fections early in life may also serve as similar risks.

The interaction of microbes and the host in the eventual develop-ment of various diseases, including asthma, is a delicate and intriguing interaction. Emerging and solid evidence indicates that children raised on farms have less asth-ma. Evidence has also shown that there may be distinct bacteria in these rural environments which can, perhaps, serve to protect from or prevent asthma. Thus, evidence is being accrued that microbes, or the environmental microbiome, may be a major determinant of the host’s eventual immune system and, as a consequence, determine the individual patient’s risk for a particular disease. This informa-tion is providing “clues” for new approaches to prevent the devel-

Figure 1 The effects of microbes on asthma.

opment of asthma (Figure 1).

We are now poised, I believe, to harness this information, and from it, develop novel strategies to move to “the next level” in asthma mechanisms and prevention of this disease. Although efforts will be ongoing to further develop of new treatments for existing asthma, our ultimate and hopefully achievable goal now needs to be on preven-tion of this disease. Until we make these necessary and appropriate inroads in prevention, the burden of asthma will continue to mount.

KEY REFERENCES1. National Asthma Education and

Prevention Program, Third Expert Panel on the Diagnosis and Man-agement of Asthma. Expert Panel Report 3: Guidelines for the Diag-nosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007. http://www.ncbi.nlm.nih.gov/books/NBK7232, accessed May 20, 2013.

2. Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, Lee WM, et al. Evidence for a causal rela-tionship between allergic sensiti-zation and rhinovirus wheezing in early life. Am J Respir Crit Care Med 2012;185:281-285.

3. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezing rhino-virus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med 2008;178:667-672.

4. Bisgaard H, Hermansen MN, Bu-chvald F, Loland L, Halkjaer LB, Bønnelykke K, et al. Childhood asthma after bacterial coloniza-tion of the airway in neonates. N Engl J Med 2007;357:1487-1495.

5. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrländer C, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011;364:701-709.

Bad bateria Viruses Fungi

Good bateria

Genetic Risk Factor

Asthma

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• The asthma epidemic affects more than 300 million patients with a global rise in prevalence, as the most common chronic childhood disease with increasing health-care costs

• Effective policies and strategy development are needed to fill this gap at the global, regional and national level

• Efforts to overcome unmet needs should focus on 4 main directions:

� Research and development � Better patient care at the global level � Increased public awareness � Asthma in the political agenda

• A “Global Fight Asthma Strategy” should be developed: � All stakeholders should be involved � A multidisciplinary and scientific approach should be used � “One Health” concept should be integrated � Next generation guidelines should be developed � A World Asthma Center and integrated asthma surveillance

network should be established � Existing know-how from successful approaches in the past

should be broadly implemented

In less than half a century, asthma, originally a rare disease, showed an epidemic increase, and has be-come a major public health prob-lem. Today, it is affecting the lives of more than 300 million people worldwide, and is expected to reach to 400 million in the next three decades. Its prevalence and impact are particularly on the rise in urbanizing regions and globaliz-ing World associated with envi-ronmental and lifestyle changes. Apart from the individual suffer-ing of patients, asthma presents a very high socioeconomic burden to health care systems and families. In addition, patient care and access to treatment is inadequate in many developing regions and countries. Effective policies and strategy de-velopment are needed to fill this gap at the global, regional, national level (Table 1).

EFFORTS TO OVERCOME UNMET NEEDSThe efforts to overcome high num-bers of unmet needs described in Chapter C1 can be grouped in four directions:

A) Research and development should be synergized and pri-oritized in order to achieve sus-tainable results on prevention, biomarkers, anti-viral vaccines,

and novel drug development, particularly for the treatment of severe asthma. There are a num-ber of barriers and obstacles in grant giving bodies to be solved in the short run (Table 2).

B) Better patient care at the glob-al level requires a worldwide approach to identify barriers for prevention and cure; devel-

op asthma registries; develop next generation guidelines (i.e. integrated care pathways); im-prove accessibility to diagnosis and essential drugs in low in-come countries; implement full environment control; realize psychological help directly and routinely without any need for consultation; implement every aspect of education of patients,

VISION, ROADMAP AND A LAND-MARKING EVENT19

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Cezmi A. Akdis President of the

European Academy of Allergy and Clinical Immunology

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primary care physicians and al-lied health personal.

C) To increase the public aware-ness, it is now essential to posi-tion asthma as one of the most important causes of chronic morbidity and health care bur-den. Asthma-focused patient organizations should be immedi-ately established in all countries. There is a lot to learn from the fight with HIV/AIDS and utilize.

D) It is not possible for the poli-ticians to remain silent at this stage, because the number of

affected individuals and fam-

ilies are huge, and health care

burden of asthma is forcing the

budgets of health systems in all

countries. A significant number

of international alliances, soci-

eties, networks and academies

are working on this (Table 3).

A WORLDWIDE STRATEGY TO FIGHT AND MANAGE ASTHMA SHOULD BE DEVELOPEDA) All stakeholders including spe-

cialists, primary care physicians, nurses, dieticians, psychologists, pharmacists, patient organi-zations, educators, industry, and policy makers should be in-volved.

B) Worldwide asthma manage-ment should be integrated with

TABLE 1

Efforts for awareness in the political bodies for allergy and asthma

• Global Allergy and Asthma European Network (GA2LEN) was established with the efforts of EAACI in 2004 as an EU FP6 Network of Excellence.

• Allergy was listed in the food and agriculture group in the EU research grants until 2007, EU accepted allergy as an important health problem in 2007 with the efforts of the EAACI and GA2LEN

• The results of the Finnish Asthma Program demonstrated that asthma burden can be substantially decreased by relatively undemanding methods doable by every country (Chapter D5) is slowly being implemented by some national health-care systems

• Asthma is included in the EU Horizons 2020 programme. Allergy is still pending and efforts are needed to include allergy

• Many one day awareness meetings have been organized or attended by patient organizations, EAACI, GA2LEN and ERS leaderships and members of the EU Parliament in Brussels during the recent years

TABLE 2

Barriers in research grants and grant giving bodies

• Lack of political awareness and low understanding and priority setting for asthma and allergy epidemics

• Curative approaches and research for prevention has not been so far efficiently supported

• Small quantities of grants have been given to hypothesis-based research, although the real need is large scale, non hypothesis based, in dept research, which is now possible with the novel developments in next generation DNA and RNA sequencing, exposome analysis, and epigenetic analysis

• Human research is receiving relatively less funding in many grant giving bodies compared to animal models

• Many major grant giving bodies had to decrease their budgets during the last years

• Negative results that are not published will be repeated and repeated


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TABLE 3

Global and transregional policies and programmes for asthma (Described in detail in Chapter D7)

• The United Nations recognized the importance of Chronic Non Communicable Diseases (NCD)

• The WHO established a 5 years NCD Action Plan 2008-2013

• GA2LEN was established as a European Network of Excellence in 2004

• Global Alliance against Chronic Respiratory Diseases (GARD)

• The International Primary Care Respiratory Group (IPCRG)

• Global Asthma Network (GAN)

• The Global Initiative for Asthma (GINA)

• Allergic Rhinitis and its Impact on Asthma (ARIA)

• The Brussels Declaration on asthma was developed in 2008

• Davos Declaration was developed in 2011

• EU Council Conclusion was developed after the prioritization of Childhood Chronic Respiratory Diseases by Polish Presidency in 2011

the “One Health” concept that acknowledges the systemic in-terconnections of human, ani-mal and environmental health in close relationship with food safety and security. In the era of climate change, resource deple-tion, land degradation, food in-security and development chal-lenges, an integrative approach is needed to ensure sustainable health. This concept strongly ap-plies to all chronic inflammatory diseases, because of a strong scientific basis of epigenetic reg-ulation of the disease genes with the influence of changing envi-ronment. Human, animal and plant health, healthy air, water and earth, food safety & security are integrative components of the “One Health” concept.

C) Next generation guidelines, such as integrated care path-ways (described in Chapter D6) should be implemented for asthma and its co-morbidities to provide structured, multi-disciplinary, region and envi-ronment-oriented, individual patient-focused, considerate on differences across cultures and

detailed patient care guidelines.

D) There is substantial experience of already established strategies and associations. We should avoid reinventing the wheel and utilize and implement the exist-ing know-how. One of the most valuable experiences in our fight with asthma is the success of the Finnish Programmes (described in Chapter D5 and D14). Based on the accumulated knowledge it is now fundamental to dissem-inate the Finnish experience to whole world, collect feedback and further improve. A step-wise asthma management plan providing best-buy measures for asthma prevention and con-trol is described in Chapter D4. Cost-efficient use of available resources, promotion of effec-tive asthma management ap-proaches and investment in in-novative models and in asthma research are important steps forward.

E) A World Asthma Center should be established with a fully inte-grated network to all national and regional asthma centers

and already established net-works, alliances, societies and Academies, aiming at worldwide asthma surveillance, strategy development and education. Prioritization of asthma is going to take place more and more in United Nations, WHO and na-tional political agendas, where chronic non-communicable dis-eases are being prioritized now-adays. Management of asthma together with other respirato-ry diseases and other chronic non-communicable diseases in these organizations may help to economize efforts in the ear-ly stage, however, full and only focus to asthma is inevitable for the success in the long run. A worldwide and integrated asthma surveillance network, using disease registries, phar-macoeconomic evaluation, as well as large biobanks should be developed.

F) Health economics studies in asthma and other life-long last-ing chronic diseases demon-strate a huge financial benefit of prevention and curative treat-ments. Particularly, prevention


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TABLE 4

Davos Declaration

Research Needs

• The causes of the epidemic increase in allergic diseases are unknown. Environmental exposures that appear to be critical factors include factors as diverse as air quality, diet and nutrition, climate, UV radiation, and direct skin contact as well as psycho-social interactions. Moreover, when genetic predisposition is taken into account, environment can provide either risk or protection.

• The effects of changes in climate, urbanization, etc. have to be anticipated. Better ways to assess spatial and temporal environmental exposure at population and individual levels are much needed and should be related to the assessment of individual genetic susceptibility.

• The interactions between microbes, pollutants, and the immune system are marginally understood.

• There is inadequate understanding of the natural mechanisms that limit acute vs. chronic disease or spontaneous resolution.

• There is a need for better subclassification of allergic disorders based on pathobiology.

• There is a need for new agents acting on specific pathways in pathogenesis with regard to new therapeutic approaches.

• There is a need for better preclinical models for translational research.

• There is a need to develop better tools for complex data analysis.

• There is a need for efficient strategies for primary and secondary allergy prevention.

• There is a need for better approaches in diagnosis and prediction of treatment responses and the monitoring of therapeutic effectiveness.

Needs for Education and Awareness

• Apart from true lack of information, there is a tremendous gap between actual existing knowledge and its effective application for the millions of people in need.

• There is a shortage of well-trained specialists in most countries.

• Education and training efforts should also be directed toward medical students at the curricular level and extended to primary care physicians, who have to be involved in a strategy for diagnosing and managing allergic diseases with such high prevalence rates of 20% of the population.

• Awareness campaigns for targeted public groups should be performed. Allied health professionals, such as nurses, school teachers, etc., should be included. Better and more effective tools to spread the available information should be developed.

• Close cooperation with patient organizations is highly recommended.

• Decision makers involved in developing and approving health policies and administration must be made more aware of the problem.

of severe asthma development and exacerbations has an im-mense effect on healthcare costs. It is now very appropriate that health insurance systems and other health-care financing models invest on research and education for primary and sec-ondary prevention and curative treatments.

G) A multidisciplinary scientific approach is essential. A group of 40 scientists and clinicians

from all around the world and all fields of allergy, asthma and re-lated disciplines gathered under the sponsorship of the Chris-tine-Kühne Center of Allergy Research and Education (CK-CARE) in Davos, Switzerland from 17 to 20 July 2011 for the first ‘Global Allergy Forum’ un-der the topic “Barriers to Cure” and developed The Davos Dec-laration (Table 4).

In a parallel action that brings

together political bodies and scientists, representatives of the European Academy of Al-lergy and Clinical Immunology, the European Respiratory So-ciety, the International Primary Care Respiratory Group, the Polish Allergy Society, the WHO Global Alliance against Chronic Respiratory Diseases, and the European Federation of Allergy and Airway Diseases Patients’ Associations were invited by the


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TABLE 5

Council of the European Union Conclusions on prevention, early diagnosis and treatment of chronic respiratory diseases in children

• Tackle the problems that constitute the biggest risk factors that could trigger a chronic respiratory disease: tobacco smoke, poor indoor air quality, and outdoor air pollution. Prevention should begin before child birth, and stop-smoking programmes for pregnant women should be intensified. Additionally, future mothers and children should be protected against exposure to tobacco smoke, in particular at home and in closed spaces.

• Strengthen efforts to reduce the disability and premature death related to asthma by fostering best practices at an international level

• Strengthen knowledge and public awareness in the prevention and treatment of these diseases. Health education of children, parents, and teachers is recognised as important in this regard, as well as training of health professionals

• Foster cooperation and exchange of best practices and support member states in implementing their policies and improving networking, particularly international research networks, to find cost-effective procedures to improve the standards of health-care systems for chronic respiratory diseases

• Develop research for a better understanding of the reasons for the increase in prevalence of chronic respiratory diseases in children and the disparities between regions and throughout Europe

Polish Minister of Health to con-vene and discuss how to prevent and control chronic respirato-ry diseases in children on Sept 20–21, 2011 (Chapter D17). These conclusions were adopt-ed during an Interministerial Conference of the 27 EU Mem-ber States, on Dec 2, 2011, and are outlined in Table 5.

KEY REFERENCES1. Ring J, Akdis CA, Behrendt H,

Lauener RP, Schäppi G, Akdis M et al. Davos declaration: Allergy as a global problem. Allergy 2012; 67:141-143.

2. Samoliński B, Fronczak A, Kuna P, Akdis CA, Anto JM, Bialoszewski AZ, et al. Prevention and control of childhood asthma and allergy in the EU from the public health point of view: Polish Presidency of the European Union. Allergy 2012; 67: 726-731.

3. Council conclusions of 2 Decem-ber 2011 on prevention, ear-

ly diagnosis and treatment of chronic respiratory diseases in children. Official Journal of the Eu-ropean Union C361 2011;54:11-13; http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri= OJ:C:2011:361:0011:0013:EN: PDF, accessed May 20, 2013.

4. Kupczyk M, Haahtela T, Cruz AA, Kuna P. Reduction of asth-ma burden is possible through National Asthma Plans. Allergy 2010;65:415-419.

5. Haahtela T, von Hertzen L, Mäkelä M, Hannuksela M; Allergy Pro-gramme Working Group. Finnish Allergy Programme 2008-2018-time to act and change the course. Allergy 2008;63:634-645.

6. Holgate S, Bisgaard H, Bjermer L, Haahtela T, Haughney J, Horne R, et al. The Brussels Declara-tion: the need for change in asth-ma management. Eur Respir J 2008;32:1433–1442.

7. Bousquet J, Schünemann HJ, Samolinski B, Demoly P, Bae-na-Cagnani CE, Bachert C, et al.

Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs. J Aller-gy Clin Immunol 2012;130:1049-1062.

8. From the Global Strategy for Asthma Management and Pre-vention. Global Initiative for Asth-ma (GINA) 2012. Available from: www.ginasthma.org.

9. One Health: Global Risk Forum, Davos, Switzerland. http://www.grforum.org/pages_new.php/one-health/1013/1/938, accessed May 20, 2013.

10. Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K, Laatika-inen T, et al. Environmental bio-diversity, human microbiota, and allergy are interrelated. Proc Natl Acad Sci U S A 2012;109:8334-8339.


The European Academy of Allergy and Clinical Immunology (EAACI) is a non-profit organization active in the

field of allergic and immunologic diseases such as asthma, rhinitis, eczema, occupational allergy, food and drug

allergy and anaphylaxis. Its scope covers both basic science and clinical medicine.

Since its establishment in 1956, EAACI has grown to become the largest medical association in Europe in the

field of allergy and clinical immunology. Its membership currently includes more than 8000 members from 121

countries, representing academicians, clinicians, and allied health professionals. In addition, EAACI includes 42

National Allergy Societies as members.

EAACI’s mission is to provide the most efficient platform for scientific communication and education in the field

of allergy and immunology, ultimately striving to ease the lives of patients suffering from these diseases. EAACI

is regarded as the primary source of expertise in Europe for all aspects of allergy.

EAACI’s activities

• Fostering science through dedicated platforms Annual Congress, Focused Meetings, Guidelines and Position

Papers

• Educating professionals (Allergy Schools; CME system; knowledge examination in allergy and clinical

Immunology; Research and Clinical Fellowships)

• Disseminating knowledge through EAACI Journals (Allergy, Pediatric Allergy Immunology, Clinical and

Translational Allergy, EAACI Newletter) and online communication platforms

• Advocating change and raising awareness among the European Union’s decision makers about the importance

of allergy and clinical immunology and the opportunities to prevent and treat allergies through Public

Campaigns and Public Declarations

EAACI’s governance and structure is derived from its Constitution and By-Laws. The governing body of EAACI

is its General Assembly representing all EAACI members. The Executive Committee acts as the main administrative

body. Important structural units that facilitate various Academy functions and activities are the Committees,

Sections, Interest Groups, the Junior Members Assembly and the Task Forces.

The Global Atlas of Asthma reviews and updates the existing

data on asthma incidence and prevalence, risk and protective

factors, pathogenic mechanisms and treatment options,

focusing on prevention and control of asthma. The paramount

role of allergy in the pathophysiology of asthma is strongly

emphasized in order to highlight the importance of our core

specialty and as a step forward for bringing the rest of the

world closer to the understanding of allergy as a major public

health/international problem.

The document is written by an international group of 80

World leaders in asthma research and is aimed to be a concise

reference for all the stakeholders and a platform for a strategic

planning for any aspect of the disease in a multifaceted way

integrating research, education and global policies.

EAACI Headquarters

Genferstrasse 21

8002 Zurich

Switzerland

Tel: +41 44 205 55 33

Fax: +41 44 205 55 39

[email protected]

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